Heart mitral valve disease (MVD) is the leading cause of death of
cavalier King Charles spaniels throughout the world. MVD is a polygenetic
disease which statistics have shown may afflict over half of all cavaliers by age 5 years and nearly
all cavaliers by age 10 years, should they survive that long.

What It Is

MVD is a degeneration of the heart's mitral valve, one of four sets of
valves in a dog's heart. As the mitral valve degenerates, the valve no
longer fully closes after each pumping action, allowing some blood to flow
backwards through them from the ventricle back into the atrium. As the
condition worsens, more and more blood is able to backflow through the
valve. In the final stages, the valve’s struts sometimes break, causing the
valve to collapse completely. MVD results in congestive heart failure in the
CKCS.

Heart failure (HF) is determined by its symptoms, which include high rates
of breathing (respiratory rates), exercise intolerance, shortness of breath
(dyspnea), increase in respiratory effort, and/or fainting.
Congestive heart failure (CHF) occurs when heart's dysfunction increases
blood pressure in the veins and capillaries, leading to fluid buildups in
the lungs (edema) or elsewhere (effusions).

About 10% of all dogs suffer from some form of heart
disease. Mitral valve disease is the most common heart disorder in older dogs of
all breeds.
However, in the cavalier King Charles spaniel, the prevalence of MVD is
about 20 times that of other breeds. Also in cavaliers, the onset of the
disease typically is much earlier in the life of the dog. It has been
reported that, once diagnosed, mitral valve disease is much more rapid in
cavaliers than in other breeds, possibly reaching a life-threatening stage
within as little as 1 to 3 years, rather than the average 3 to 5 years.
To a lesser extent, cavaliers also suffer from deterioration of their
tricuspid valves.
More...

Diagnosis

All cavaliers should be screened for heart murmurs once a year beginning
at age 1 year. Once MVD is detected, its progression can be monitored with stethoscopic examinations (auscultations), x-rays, echocardiograms, and
color Doppler echocardiograms. If a heart murmur is detected, it should be
confirmed in 3 to 6 months. If it still is detected, the dog is considered
probable for MVD. More...

Symptoms & Treatment

The progression of mitral valve disease can be rapid or slow. In most
cavaliers, the disease shows a gradual progression in the loudness of the
murmur and to more serious symptoms, in as little as 2 years after first
detecting the murmur. Drugs may help to minimize the symptoms, but
eventually the drugs may be unable to control them. The drugs prescribed for
cavaliers with MVD can sometimes have severe adverse side effects, and blood
chemistry should be done routinely to monitor their effects upon the
kidneys, liver, and other internal organs. Severe symptoms of MVD in some
cavaliers will appear more quickly, although previously having been stable.
The ultimate consequence of the disease is heart failure.
More...

Breeders' Responsibilities

Due to the pervasiveness of MVD in the breed worldwide, cavalier King
Charles spaniels under the age of five years should not be bred (with one
limited exception -- see MVD Breeding Protocol). Also, no
cavalier should be
bred after age five years if it developed an MVD murmur before the age of
five years. Any littermates of breeding stock having early-onset MVD (mitral
valve murmurs before age 5 years) should be taken into very serious
consideration. All CKCS breeding stock should be examined by
board certified
veterinary cardiologists at least annually and cleared by the veterinary
specialists for MVD, the closer the examination to the breeding the better.
It is recommended that all cavaliers, breeding stock or not, be examined
annually by board certified veterinary cardiologists after age one year. See
the current list of health clinics for upcoming cardiologist examinations.

Degenerative mitral valve disease (MVD)* is the leading cause of death of
cavaliers. It is a highly-heritable, polygenetic acquired heart disease which, statistics
show, afflicts over half of all cavalier King Charles spaniels by age 5
years and
greater than 90% by age 10+ years, should they survive that
long.

Veterinary cardiologists began compiling statistics on cavaliers with MVD
murmurs in the United Kingdom in 1990. Since then, cardiologists have
examined the hearts of many thousands of cavalier King Charles spaniels at
health clinics held by CKCS breed clubs in the UK, Canada, the USA, and
elsewhere. From the data they have compiled, they have found that the
percentage of CKCSs which develop MVD murmurs increases at a rate of about
10% per year. So, roughly 10% of cavaliers by age one year have MVD murmurs,
and 20% aged between one and two years have murmurs, and so on for each age
level. Specifically, the statistics show that more than half of all
cavaliers aged five years have murmurs, and it is the very rare cavalier at
age ten years which does not have, at the very least, a low grade MVD
murmur.

Mitral valve disease is a uniquely serious, life-shortening problem for
cavalier King Charles spaniels and is their leading cause of death. About
10% of all dogs suffer from some form of heart disease. MVD is
the most common heart disorder in older dogs of all breeds. Several smaller breeds of
dogs typically are predisposed to suffer from MVD. However, in most all
breeds, MVD does not result in heart failure, causing death, because MVD
does not develop early in a dog's life, and does not progress rapidly.

In the cavalier King Charles spaniel, statistics have shown that the
prevalence of MVD is about 20 times that of other breeds of dog. Also in
cavaliers, the onset of the disease typically is much earlier in the life of
the dog, with over half of all CKCSs having developing MVD by their fifth
birthday, as noted above. For most breeds, MVD is an old-age disease, and
the age of onset is between 10 and 15 years of age.

It has been reported that, once diagnosed, MVD is much more rapid in
cavaliers than in other breeds, possibly reaching a life-threatening stage
within as little as 1 to 3 years, rather than the average 3 to 5 years.
Studies of cavaliers have concluded that it has an hereditary basis and is
"polygenetic", meaning that more than one gene can be the cause.

Some research has indicated that MVD in the CKCS may be attributed to
a chronic state of inflammation, as evidenced by measurements of
immunoglobulin antibodies and glycoprotein and complement proteins
particularly associated with immune responses to inflammation. See
this 2014 Italian study. In a
2006 USA study, researchers found that, compared with controls, dogs
with chronic valvular disease had higher plasma concentration of
C-reactive protein (CRP). In veterinary medicine, CRP concentration has
been shown to increase in inflammatory states, such as pancreatitis.
Other research by Dr. Brendan Corcoran indicates that the damaging of
the CKCS mitral valves is due to a life-long traumatic condition
combined with the dog's inability to appropriately repair that damage.
He has coined the term, "dyscollagenesis" (as opposed to fibrosis)
meaning a chronic reduction in collagen production and a disorganization
and failure of maturation. See
his 2010 report.

MVD is a degeneration and fibrosis of the heart's mitral valve, one of
four sets of valves in a canine's (and a human's) heart. It is the valve
which is designed to prevent the backflow of blood from the left ventricle
into the left atrium. It consists of a set of double flaps, called
"leaflets", that open and close like a set of one-way doors at appropriate
times during each heart beat. Normal mitral valve leaflets are comprised of
three layers of tissue (atrialis, fibrosa, and spongiosa) and are very thin
and nearly transparent. They are connected by tendons (chordae tendineae) to
the muscles of the left ventricle.

Blood flows through the pulmonary veins from the lungs into the left
atrium, one of the chambers of the heart. The mitral valve is located
between the left atrium and the left ventricle, another chamber in the
heart. The valve's action is governed by the movement of blood as it is
pumped from the atrium and into the ventricle. The two leaflets of the mitral
valve are con rolled by the tendons, which serve as thin "struts" shaped
much like the chords of a parachute.As the diseased mitral valve
degenerates, myxomatous transformation -- the development of excess connective
tissue that thickens the spongiosa and separates collagen bundles in the
fibrosa -- causes the valve to lose its flexibility, its leaflets thickening
and shortening, its fibers stiffening, and its chordae tendineae elongating.
The leaflets no longer fully close after each pumping action (see photo
of at
right above), allowing blood
to jet backwards through them from the ventricle back into the atrium. As
the condition worsens, advanced lesions cause the leaflets to fold, invert,
and displace toward the left atrium. In the photo at right, LA is the
heart's left atrium, LV is the left ventricle, and in-between, the opening
of the mitral valve shows thickened, shortened leaflets which no longer
fully close. In the photo at the left*, a
healthy mitral valve leaflet at the top is compared with a damaged valve
leaflet below. More and more blood is able to backflow
through the damaged valve, causing both the left atrium and the left ventricle to
enlarge. In the final stages, the valve’s chordae tendineae sometimes
rupture, and if they are major chords, causing the valve to collapse
completely.

* Photo credit to
Dr. Brendan Corcoran, University of Edinburgh's Royal (Dick) School of
Veterinary Studies.

Apart from the mitral valve itself, the disease has severe consequences
for the rest of the heart and the lungs. The increased pressure in the left
atrium decreases blood flow from the lungs to the heart, resulting in
congestion in the pulmonary veins, ultimately causing fluid, called
pulmonary edema, to leak out of the capillaries into the pleural cavity of
the lungs. As the left atrium enlarges, cardiac output declines. Heart
failure (HF) is determined by its symptoms, which include high rates of
breathing (respiratory rates), exercise intolerance, shortness of breath
(dyspnea), increase in respiratory effort, and/or fainting. Congestive
heart failure (CHF) occurs when heart's dysfunction increases blood pressure
in the veins and capillaries, leading to fluid buildups in the lungs (edema)
or elsewhere (effusions).

The
decrease in output forces the body to compensate by activating angiotensin-converting
enzyme (ACE) to excessive levels, forming angiotensin II, which causes the
veins and arteries to constrict. Angiotensin II also releases aldosterone,
resulting in sodium and water retention. The left atrium enlarges first,
followed by an enlarged left ventricle and the pulmonary veins. The heart
enlargement may cause a tear in the left atrium, which usually results in
immediate stoppage of blood flow.

To a lesser extent, cavaliers also suffer from
deterioration of their tricuspid valves. For an in-depth on-line seminar
about the symptoms, diagnosis, progression, and treatment of mitral valve
disease,
watch Dr. Andrew Beardow, with his terrific active
graphics, explain MVD.

As MVD progresses towards congestive heart failure (CHF), early symptoms which may occur are exercise
intolerance, breathlessness, a distended abdomen,
lack of appetite, restlessness at night, weight loss, and fainting. Breathlessness is a most common sign, starting as
excessive panting on exercise. As breathing difficulties become more severe,
the dog may sit or stand, holding its elbows away from the chest, and it may
be reluctant to sit down.

Productive coughing or a hacking cough can be an early symptom
of CHF, due to the enlargement of the heart.

As greater quantities of blood leak through the damaged mitral valve from
the left ventricle back into the left atrium of the heart, the atrium
gradually begins to swell and enlarge (see x-ray of enlarged heart at right) -- called myocardial remodeling -- to
accommodate the overload of blood, and there is a reduction in the ability
of the ventricle to provide sufficient blood to meet the demands of the rest
of the body. The heart then has to pump harder and faster, to meet those
demands.

Also, due to the increasing lack of blood being pumped throughout the
body, non-essential blood vessels begin to shut down, to conserve blood flow
for vital organs, such as the brain and the heart itself, and reducing the
flow to the skin and the kidneys. This causes the skin to pale and the
kidneys to retain fluids in the circulation, because the circulation
identifies the low cardiac output as dehydration. The excess fluid retention
results in further stretching of the heart and greater mitral valve leakage.
If the tricuspid valve is also affected,
the retained fluid, called ascites, is squeezed into other body tissues,
the liver, chest, and peritoneal cavity of the abdomen. See photo below
right of dog with ascites.

The shut-down of the distant blood vessels also has the effect of causing
the left ventricle to beat against a higher resistance, causing another
increase in mitral valve leakage.

The enlarged size of the heart fills the voids in the
chest cavity and causes pressure on the main airway -- the left main
bronchus, resulting in a dry, hacking cough and breathlessness. It may even
cause the trachea to collapse.* However, in a
June
2011 preliminary study report, researchers were unable to confirm an
association between left atrial enlargement and airway collapse in dogs with
MVD. The study suggested that airway inflammation was common in the affected
dogs.

Also, the overload of blood in the left
atrium creates increased pressure back into the pulmonary veins, which drain
into the left atrium from the lungs. When a critical pressure is reached,
flooding of the lungs can occur, with pulmonary edema.

Cavaliers with murmurs of between Grade 3 and Grade 6 may display
episodic weakness of the hindquarters, ataxia, or collapse, which is called presyncope, or combined with loss of consciousness, which is called syncope,
due to a sudden decline in blood flow to the brain. See
Syncope for a
discussion of this disorder and its causes.

A loss of appetite, resulting in possibly severe weight loss (called
cardiac cachexia), particularly of muscle mass, is another symptom of
advanced MVD.

The ultimate consequence of mitral valve disease is heart
failure. The median survival period for dogs once they develop severe
congestive heart failure (CHF) due to MVD is approximately seven months,
with 75% of the dogs dead by one year. For dogs with less severe CHF, the
median survival period is one year, with 75% of the dogs dead by 21 months.
However, the CKCS has a more accelerated version of MVD, and they typically
progress more rapidly to heart failure.

As the cavalier nears death from MVD, often the dog will
display a severe air hunger and uses all of its remaining energy just trying
to breathe.

In a 2005
report, cardiac researchers at Tufts University's Cummings School of
Veterinary Medicine devised a survey that may prove to be similarly useful
in evaluating the quality of life for dogs with heart disease. Known as
"FETCH" (Functional Evaluation of Cardiac Health), the survey asks the dogs'
owners to rank aspects of their dog's health on a scale of 0 to 5.
Veterinarians are then able to assess the animal's perceived quality of
life, which may inform decisions about treatment, nutrition or even
euthanasia. Researchers found that the FETCH scores correlated well to the
International Small Animal Cardiac Health Council (ISACHC) classification
for disease severity.

Cavaliers should be screened for heart murmurs* annually,
beginning at age one year. Once mitral valve disease (MVD) is detected, its progression can be
monitored with stethoscopic examinations (auscultations), x-rays,
respiratory rates (breaths per minute while resting or asleep),
echocardiograms, and color Doppler echocardiograms. If a cavalier's heart murmur is
first detected by a general practice veterinarian, it should be confirmed within 3 to 6 months by a
specialist, preferably a board certified veterinary cardiologist. If it
still is detected, the dog has MVD.

Also, ask the cardiologist about the American College of
Veterinary Internal Medicine (ACVIM) Registry of Cardiac Health (ARCH), a
new registry and database for canine hearts examined by board certified
cardiologists. See the details on the
ARCH website.

In a 2009 "Consensus
Statement" published by a panel of the board certified veterinary
cardiologists of the American College of Veterinary Internal Medicine
(ACVIM), they state:

"Consensus recommendations:

"Small breed dogs, including breeds with known
predisposition to develop CVHD [chronic valvular heart disease] (e.g.,
Cavalier King Charles Spaniels,
Dachshunds, Miniature and Toy Poodles) should undergo regular evaluations
(yearly auscultation by the family veterinarian) as part of routine health
care.

"Owners of breeding dogs or those at especially
high risk, such as Cavalier King Charles Spaniels,
may choose to participate in yearly screening events at dog shows or other
events sponsored by their breed association or kennel club and conducted by
board-certified cardiologists participating in an ACVIM-approved disease
registry."

The first indication
of MVD which is detectible apart from a
echocardiograph (ultrasound) examination, is the presence of a soft whistling sound, called a "murmur", which can be
heard by a veterinarian using a stethoscope, which is called auscultation.
The murmur sound is caused by the turbulent flow of blood jetting backwards
through the damaged leaflets of the mitral valve from the left ventricle,
into the left atrium. As simple a device as the stethoscope may seem to be,
many cardiologists consider that auscultation is the best screening test
there is for the identification of
the
presence of mitral valve regurgitation.

Even if the veterinarian does not hear a murmur, he might report hearing a
"systolic click" when he examines the dog with his stethoscope. Veterinary
cardiologist Dr.
James Buchanan of the University of Pennsylvania has stated that
"systolic clicks occur twenty-five times more frequently in cavaliers than
other breeds and may be a precursor to a murmur showing up a few years
later."

Radiography (x-ray) is used to determine if the heart is enlarged
(particularly the left atrium and left ventricle), if the veins from the
lungs to the heart are distended, or if fluid is beginning to develop in the
lungs.* X-rays also will show any enlargement of
the pulmonary vein, a classic symptom of congestive heart failure (CHF).

*X-ray is the only diagnostic device for
detecting fluid in the dog's lungs.

Once MVD is diagnosed, annual x-rays are very useful in charting the
progression of the disease. Mild to moderate heart enlargement indicates
moderate progression, with the heart compensating for the effects of mitral
valve disease by enlarging. When moderate to severe heart enlargement
develops, early clinical signs such as breathlessness or rapid breathing would be expected. Severe
heart enlargement indicates impending heart failure.

Cardiologists use x-rays to evaluate the size and shape of the heart in
order to assess the severity of MVD.
They
measure the the length and width of the heart and compare those dimensions
to the number of veterbrae from T4 to T12, to calculate the Vertebral Heart
Score (VHS). See
this
YouTube video for details. A diagram showing how the VHS is calculated
is
here. This is called the Buchanan VHS method, devised
by Dr. James W.
Buchanan, a pioneer in the research of MVD in cavaliers, in
1995. In
a
2012 study, a team of Spanish researchers, issued a new VHS measurement,
called Objective VHS. The radiograph image at the right
above shows vertebral heart scale measurements.

Periodic x-rays of the cavalier's heart, showing the rate of its
enlargement, are viewed by many cardiologists as an effective way to
anticipating the onset of heart failure (HF). (The series of x-rays at
left shows the increase in heart size of one cavalier over 5 years. --
Courtesy of the Royal Veterinary College.)

In
a September 2011 study of 94
CKCSs*, an international team of cardiologists
concluded that the difference in the vertebral heart scale per month was a
useful measurement for detecting the onset of HF.

An
ever increasing respiratory rate, while the dog is asleep or resting, which
approaches or exceeds 30 breaths per minute, is an indication that the dog is
approaching heart failure. Once a dog is diagnosed with MVD and
the disease has been progressing, the treating veterinarian may ask the
dog's owner to periodically count the number of breaths the dog takes per
minute while asleep or resting, and to keep a record of those counts. In an
October 2012 study, researching cardiologists found that healthy adult
dogs generally have mean sleeping respiratory rates of less than 30 breaths
per minute and rarely exceed that count.

While the dog is resting or sleeping (preferably sleeping), count the
number of breaths the dog takes in 15 seconds. Then multiply that number by
four to get the number of breaths per minute. If that respiratory rate
increases by more than 20 percent over 2 to 3 days, or exceeds 30 breaths
per minute, many treating veterinarians would advise the dog's owner to
report to them.

In a 2011
study which compared the effectiveness of (a) respiratory rate, (b)
natriuretic peptide concentration, and (c) echocardiogram, in predicting
heart failure, the respiratory rate count was more accurate
than both of the other procedures. The researchers stated:

"Only
respiratory rate predicted the presence of CHF ... with high accuracy.
... Home monitoring of respiratory rate is simple and very useful in the
assessment of CHF in dogs with either DCM or MVD."

Every cavalier owner can and should learn this very simple procedure
of how to count the breaths of their MVD-affected dogs while they are
sleeping or at rest. Several cardiologists are recommending that
owners become familiar with their MVD-affected cavaliers’ normal resting
breathing rate and effort and keep logs of their sleeping respiratory rates,
to establish a baseline rate for each dog,
and report when the dogs’ rates increase to consistent rates approaching or
above 30 to 40 breaths per minute. For example, the University of
Pennsylvania’s veterinary school advises
in a handout available on-line:

“When your dog is at rest, watch their sides rise and fall as they
breathe normally. One rise and fall cycle is equal to one breath. Count the
number of breaths they take in 15 seconds, then multiply this number by 4 to
get total breaths per minute. For example, if you count 8 breaths in 15
seconds, that is equal to 32 (8 x 4) breaths per minute.
A normal dog at
rest should have a respiratory rate less than 40. If you notice this number
increasing consistently, or notice an increase in the effort it takes to
breathe, contact your veterinarian.”

The vet school at Texas A&M University also has
published a handout(right) explaining how to keep track of dogs’ respiratory rates.
An excellent
YouTube video shows when
and
how every cavalier owner can count the breaths of their MVD-affected dogs
while they are sleeping or at rest.

Echocardiography (ultrasound scanning) is a beam of ultra-high frequency
sound directed at the heart, and is used to evaluate heart size, function,
and valve appearance. The earliest indications of MVD are outwardly invisible and silent and
can only be observed by the ultrasound. Echo scans can demonstrate the thickened valve
leaflets and their abnormal movement, such as prolapse (MVP).

The echo image at right shows a dog's heart with MVD.
LA-left atrium; LV-left ventricle; MV-mitral valve, septal leaflet. Note the
thickened free end of the mitral valve leaflet at the left of the valve.

The color
Doppler can evaluate the direction and velocity of blood flow, quantifying
blood leakage. It can be used to distinguish MVD from benign murmurs in
ambiguous cases. The Doppler may detect leakage before it is audible as a
murmur. However, trivial regurgitation of blood through the mitral valve may
be present in as many as 50% of normal dogs. In such cases, however, there
is no MVP or valve thickening present. (The color Doppler view below
shows red blood at the top, regurgitating from the mitral valve of this
CKCS.)

During echo exams, the operator typically also will take
measurements of the heart to determine if it has enlarged and the likely onset of heart
failure (HF). See this
2002
report by Drs. Jens Häggström, Kjerstin Hansson, Clarence Kvart,
and the 2012
PREDICT Cohort Study, for more information.

An advanced version of the Doppler ultrasound, called Tissue
Doppler Imaging (TDI), has been found to be more sensitive than
conventional ultrasound in human medicine. TDI reportedly has been able
to detect early myocardial dysfunction in patients with a left
ventricular (LV) volume overload induced by mitral regurgitation (MR).
TDI also has been tested on dogs and also has been found in a
December 2005 study to detect congestive heart failure (CHF). A
still more advanced version, known as color Doppler (CD) TDI, was tested
in a
study published in January 2015 by South Korean researchers. They
found that CD TDI was more useful in detecting CHF and that one TDI
variable (TDI-derived E/Em sept), which evaluated diastolic function,
could be an important predictor of CHF in dogs with MVD.

For cavaliers' hearts, it is recommended that ultrasound scanning be
conducted by specialists, preferably board certified veterinary
cardiologists.

As of December 2011, Drs. Julia Sargent, Virginia Luis Fuentes,
and Holger Volk, of the Queen Mother Hospital for Animals at the
Royal Veterinary College in the UK, have developed a new echocardiographic
scoring system to grade the severity of mitral regurgitation in chronic
mitral valve disease, based upon a number of different measurements that
they believe can offer more reliable information on the severity of MVD.
They are testing their new scoring system by comparing it to cardiac
magnetic resonance imaging (cMRI), which is considered the most reliable
test for quantifying valve disease in humans.

Due to the necessity of anaesthetizing the dogs for the cMRIs, the
researchers are seeking to recruit dogs already scheduled for MRIs for other
reasons, such as syringomyelia examinations. All dogs will undergo
conventional echocardiography to assess their heart disease prior to
anaesthesia and the MRI scan, and only dogs with stable heart disease will
be recruited.

The researchers expect to be able to provide more accurate information
for the individual dogs on the severity of their valve disease as a result
of the MRI scan, and new echo score. They believe that the scoring system
should be particularly useful for standardizing the severity of MVD at entry
for clinical studies.

Electrocardiography (ECG or EKG) is a diagnostic tool
that measures and records the heart's electrical activity. Multiple,
advanced resting electrocardiographic techniques have been applied to humans
to detect cardiac diseases before onset of symptoms or changes in the
standard ECG. In a June 2011 study
by Slovenian and Danish researchers, they were able to use advanced ECG to
predict the severity of mitral regurgitation in dogs with MVD. They
reported:

"Our results indicate that for a cut-off criteria of MR
[mitral regurgitation] 50% jet the five selected ECG parameters could
predict the severity of MR caused by MMVD in CKCSs with sinus rhythm with
sensitivity 65% (78% with age inclusion) and specificity 98% (92% with age
inclusion) (P < 0.05)."

There has been much research into attempting to diagnose MVD, and more
particularly, to diagnose the onset of heart failure (HF) in dogs, by
measuring "cardiac biomarkers", such as plasma concentrations of the natriuretic peptides: atrial
natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Natriuretic
peptides are hormones manufactured and secreted by areas of the heart. ANP
is responsible for the regulation of blood pressure and body fluid
homeostasis.

In
a 2014 Swedish study of 535 healthy dogs of nine breeds, researchers
found that CKCSs and German shepherds had the highest median ANP
concentrations, twice the median concentration in the breed with the lowest
concentration, the Doberman Pinscher.

A
test of natriuretic peptides measures the quantity of the natriuretic
peptides in the dog's blood. Elevated levels of these natriuretic peptides
in the blood may be directly related to heart defects, and natriuretic
peptides in the blood become elevated only after the heart has to pump
harder to compensate for the disorder. In particular, BNP is secreted by the
left ventricle in response to heart wall stretching or stress.

A 2003 study (conducted by
Drs.
Kristin A. MacDonald,
Mark D. Kittleson,
Coralie Munro, and Philip Kass of the University of California at Davis) has
shown a positive correlation between BNP and heart disease and CHF in dogs. In that study, BNP increased with the
progressively increased severity of mitral valve disease and CHF. For every
10-pg/mL increase in BNP, the 2003 study's dogs' mortality rate increased
approximately 44% over the four months of the study. In a
2005 study, Drs.
William E. Herndon, Justine A. Lee, Kenneth J. Drobatz,
and Matthew J. Ryan concluded that "With further investigation, this
new BNP assay may someday provide a widely available noninvasive diagnostic
test with rapid turnaround time to help diagnose and/or treat heart disease
and congestive heart failure in the dog."

owever, in earlier studies (1994 and
1997) conducted by Drs. Jens Häggström, Kjerstin Hansson, Clarence Kvart, and others, the researchers
have suggested that BNP levels in cavaliers with mitral regurgitation did
not rise as dramatically as in humans, and that N-terminal (NT)-proANP (NT-proANP)
may better reflect the severity of mitral regurgitation in cavalier King
Charles spaniels than NT-proBNP tests.

Four trademarked names for NT-proBNP tests are Canine CardioCare
(Veterinary Diagnostics Institute), Canine VetSign CardioSCREEN (Guildhay
Ltd.), Cardiopet proBNP (IDEXX Laboratories), and Antech Cardio-BNP (Antech
Diagnostics). There have been studies showing the effectiveness of these types of
tests for dogs suffering from asymptomatic occult dilated cardiomyopathy
(DCM), which is not the same disorder as MVD and is not known to be a
genetic problem for cavalier King Charles spaniels.

Whichever test (NT-proBNP or NT-proANP) is found to be more accurate for
detecting MVD, it is believed by some researchers that the test may be
useful in assisting examining veterinarians in deciding whether or not
detected heart murmurs are innocent or are pathologic in nature. However, in
a 2007 study of 54 CKCSs by
Drs. Tarnow, Pedersen, Kvart, and others from
Denmark and Sweden, they found that "Natriuretic peptides are elevated in
cavalier King Charles spaniels with congestive heart failure but not in dogs
with clinically inapparent mitral valve disease."

In a May 2008 report by
Drs.
Mark A. Oyama,
Philip R. Fox,
John E. Rush, Elizabeth A. Rozanski, and Michael
B. Lesser of 119 dogs, they found
that "Serum NT-proBNP concentration was significantly higher in dogs with
cardiac disease than in control dogs, and a serum NT-proBNP concentration >
445 pmol/L could be used to discriminate dogs with cardiac disease from
control dogs with a sensitivity of 83.2% and specificity of 90.0%. In dogs
with cardiac disease, serum NT-proBNP concentration was correlated with
heart rate, respiratory rate, echocardiographic heart size, and renal
function." They concluded that, "For dogs with cardiac disease, serum NT-proBNP
concentration could be used to discriminate dogs with and without
radiographic evidence of cardiomegaly and dogs with and without congestive
heart failure." And that, "Results suggested that serum NT-proBNP
concentration may be a useful adjunct clinical test for diagnosing cardiac
disease in dogs and assessing the severity of disease in dogs with cardiac
disease."

In a May 2009 report
from Sweden, the researchers concluded: "Plasma concentrations of the
natriuretic peptides measured at re-examination could predict progression in
regurgitant jet size."

In a
2012
study of 1,134 dogs, including 37 cavaliers, Stephen J. Ettinger,
Giosi Farace, Scott D. Forney, Michelle Frye, and Andrew
Beardow concluded that "This biomarker [NT-proBNP] may be a useful
tool for staging of cardiac disease and identifying cardiac-related coughing
or dyspnea in this species."

In a
2013 study of 36 dogs, none being CKCSs, a team of Japanese researchers
concluded: "These results indicated that plasma ANP rose with an increase in
the volume overload of the left side of the heart. Plasma ANP discriminated
cardiomegaly from non-cardiomegaly caused by asymptomatic MMVD. We conclude,
therefore, that plasma ANP concentrations may be a clinically useful tool
for early diagnosis of asymptomatic MMVD in dogs."

In an
April 2013 report, a team of German veterinary cardiologists studied 352
dogs and found that: "NPs [natriuretic peptides] in canine MMVD are useful
to discriminate between asymptomatic dogs and dogs with CHF. Due to a large
overlap of NP-concentrations between the groups, NPs do not seem to be
useful to differentiate between dogs in stages B1 and B2. Interpretation of
NT-proBNP and proANP values should include consideration of sex-specific
differences."

Finally, in a
July 2014 report, a Swedish/Finnish/Danish team examined 78 cavaliers with
MVD and found that the risk of CHF increased with NT–proANP
concentrations above 1000 picomoles per later (pmol/l). They also found
that the risk of the onset of congestive heart failure (CHF) increased
with a heart rate greater than 130 beats per minute and a mitral valve
murmur grade of 4 to 6. In
an October 2014 study of 291 dogs, including 38 cavaliers,
researchers once again found that plasma NT-proBNP concentrations were
higher in dogs in congestive heart failure (CHF) than in dogs with
non-cardiac respiratory distress.

Nevertheless, it appears that veterinary cardiologists and other
cardio-specialists should be quite capable of detecting mitral valve
prolapse (MVP) murmurs and distinguishing between them and flow murmurs or
other innocent varieties of heart murmurs. Since ANP and BNP in the blood becomes
elevated only after the heart has to pump harder to compensate for the
disorder, the question then is: When does the heart start working so hard
that BNP levels start to go up? In the cavalier King Charles spaniel's
version of heart defects -- mitral valve disease due to deteriorating valve
flaps -- there are no immediate external symptoms. It is not yet clear from
research studies thus far, as to whether the heart becomes labored enough to
produce increased levels of BNP before auscultation is able to detect the
murmurs from minimal backflow of blood leaking through the mitral valve
flaps. Advocates of ANP and BNP testing do represent that that studies of
ANP and BNP and cardiomyopathy show that ANP and BNP are elevated before the onset of signs and
murmur. But it does not yet appear that ANP or BNP testing necessarily is an any earlier
warning system for MVD than auscultation.

"For conditions such as mitral valve disease, this test
may be of limited value because a diagnosis can be readily made by thorough
auscultation and documentation of a heart murmur. In these cases, the assay
also has limited utility in determining disease severity; thoracic
radiography is preferred."

One possible uniquely valuable use for natriuretic
peptides tests is if the dog is approaching heart failure (HF)
without any symptoms. In that case, natriuretic peptides tests, combined
with "Left Chambers on Aorta ratio" greater than 4,5, the veterinarian may
begin administering ACE inhibitors, pimobendan, and other drugs immediately
even though the dog is asymptomatic. See Dr. Gerard Le Bobinnec's
proposal in this report
to the 2010 WSAVA Congress. See, also, the
2012
report of the PREDICT Cohort Study, which found that measurements of
left heart size (using the "left atrial to aortic root dimension ratio [LA:Ao]")
and plasma NT-proBNP concentration independently estimate risk of
first-onset of CHF in dogs with MVD. It correctly predicted first-onset of
CHF in 72.5% of cases out of 82 dogs, which included cavaliers.

Dr. Oyama has stated that natriuretic peptide tests may
also be useful to properly diagnose a dog known to suffer from congestive
heart failure and also is in respiratory distress. He said that, “When dogs
come into veterinary hospitals in respiratory distress, it’s sometimes
difficult to know if they are having a respiratory or heart problem. Such a
test could speed effective treatment and also help decide if a dog should be
referred to a veterinary cardiologist before undergoing more expensive
testing.” Dr. Adrian Boswood of the Royal Veterinary College has suggested
that the NT-proBNP assay may have some value in predicting the future life
span of dogs in congestive heart failure.

---cardiac troponin I (cTnI)

Other cardiac biomarkers include cardiac troponin I (cTnI),
and high-sensitivity cardiac troponin I (hscTnI), and
sodium-calcium exchanger (NCX-1), and leptin.
Several studies of cardiac troponin I (cTnI) have shown increases in cTnI
concentrations in dogs with poor prognoses, and that cTnI has potential in
assessing the prognosis and severity of MVD and enlargement of the heart.
See the 2009 study, the
January 2010 study, the
June 2010 study, and the
April 2013 study. In a
February 2012 study,
high-sensitivity cardiac troponin I (hscTnI), in combination with N-terminal
pro-B-type natriuretic peptide (NT-proBNP) concentrations, has been
examined. The researchers concluded that:

"Survival times were shortest in dogs in which both serum
hscTnI and NT-proBNP were increased. hscTnI and NT-proBNP increased more
rapidly in dogs that died of cardiac disease. Conclusions and Clinical
Importance: Serum hscTnI has prognostic value in dogs with DMVD. Measurement
of NT-proBNP and hscTnI is prognostically superior to measuring either
alone. Serial measurement strategies provide additional prognostic
information."

---sodium-calcium exchanger (NCX-1)

Sodium-calcium exchanger
(NCX-1) is being examined as an alternative to natriuretic peptides because
NCX-1 appears to better differentiate between heart failure and renal
failure. See this 2010 South Korean
report. Also, leptin, a protein produced by fat tissues and
associated with canine body fat, was found in an
August 2011 UK report to be more
highly concentrated in dogs with congestive heart failure.

---aldosterone concentration (UAC)

In
a November 2012 report, researchers found that left ventricular heart
enlargement in dogs with MVD is associated with a decrease in the serum
concentration of a marker of collagen type III turnover, and an increase in
urinary aldosterone concentration (UAC). They also reported
that both serum N-terminal procollagen type III
concentration and UAC were higher in cavalier King Charles spaniels than in
other breeds when other measured variables were controlled for.

However, in an
April 2013 study of
50 dogs (including 20 CKCSs), the researchers reported that:

"Cardiac fibrosis and arteriosclerosis in dogs with MMVD
are reflected by circulating cTnI [cardiac Troponin-I] concentration,
but not by aldosterone concentration or renin activity. Cardiac
troponin I could be a valuable biomarker for myocardial fibrosis in dogs
with chronic cardiac diseases." (Emphasis added.)

In
a July 2013 study of 120 dogs,
including 92 cavaliers, by an international team of
cardiologists, the researchers found that cavaliers had higher
concentrations of serum serotonin (serum 5HT) than other
breeds not predisposed to mitral valve disease, and that serum 5HT
concentrations decreased with increased left atrial enlargement. They
concluded that, "the finding of higher serum 5HT concentrations in dogs
predisposed to MMVD (CKCS) and dogs with mild MMVD suggests that alterations
in 5HT signaling might play a role in progression of early stages of MMVD."

In a 2009 study, some
of the same researchers found, "Dogs with DMVD had significantly higher
serum 5HT concentrations when compared with large breed control dogs.
Healthy CKCS dogs had significantly higher serum 5HT concentrations than
other healthy dogs predisposed to DMVD."

In a January 2013 interview with AKC's Canine Health
Foundation, board certified cardiologist Dr. Mark Oyama of
University of Pennsylvania's veterinary school, said:

"Our research involving serotonin and other pathways involved in the
development and progression of disease are ultimately targeted towards
discovering the underlying abnormalities that produce mitral valve disease
in dogs. If serotonin and other pathways contribute to disease formation
blockade of these pathways could result in reduction in disease development
and progression."

In a
July 2014 report, the international team found that platelet serotonin
was elevated in cavaliers compared to other breeds, and that left
ventricular myocardial and mitral valve leaflet tissue in deceased MVD dogs
was elevated compared to dogs which died without cardiac disease. See also
this
August 2014 report finding serotonin concentration high in cavaliers.

---antidiuretic hormone (ADH)

Antidiuretic hormone (ADH) is produced by the
hypothalamus and contributes to regulating blood pressure and blood plasma
osmolality. High levels of ADH are believed to play a role in the
development of congestive heart failure (CHF) in humans. For humans, an
enzyme immunoassay (EIA) kit is used to quantify ADH levels. In a
September 2013 study, a team of cardiologists from Oregon State
University used EIA kits to compare the ADH concentrations in 6 healthy dogs
and 12 with CHF. They researchers concluded that EIA kits can be used to
determine ADH concentrations in dogs and that the dogs in CHF had
significantly higher ADH concentrations than did the healthy dogs.

---histamine concentration

In a
May 2014 report, Japanese cardiologists found that histamine
concentration was higher in the population of dogs with MVD compared with
the healthy controls.

---enzymes and growth factors

In
an October 2014 study, researchers found that mitral valve and
myocardial protein and gene expression of the enzymes matrix
metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and
transforming growth factor-β (TGF-β) and plasma MMP and TGF-β
concentrations appear to play a local role in the development of
advanced MMVD.

In
a 1996 study, Swedish researchers Lennart Swenson, Jens Häggström,
and Clarence Kvart, reported that MVD in cavaliers "is a polygenic
threshold trait and that sex of the offspring influences threshold
levels."

A team of veterinarians from Denmark, Sweden,
Germany, England, and France reported in
September 2011 that they have identified two specific
locations on cavaliers' chromosomes CFA13 and CFA14 which are associated the
breed's hereditary mitral valve disease. They grouped 139 cavaliers with
early-onset MVD and 102 old CKCSs with no or mild signs of MVD as controls. Then
they conducted a genome-wide association study to find specific locations
associated with development of MVD. They also stated:

"We will initiate studies of the most promising candidate
genes in the 2 candidate regions which hopefully will lead us to the
mutations affecting the development of mitral valve disease."

However, in November 2011, a team of UK cardiologists and geneticists
divided 36 CKCSs into groups of early and late onset MVD and assessed
whether the distinction is determined by a small number of genetic factors.
They report that they came up dry. They
concluded:

"There were no regions of highly discrepant homo/heterozygosity
in the two groups. Similarly, there was no evidence for loci associated with
mitral valve murmur in a genome-wide association study. This analysis
suggests that familial occurrence of mitral valve murmur in the CKCS breed
is not due to a single major gene effect, indicating that breeding
strategies to eliminate the disease cannot be based on genotype information
at this time."

This seems to contradict the much more successful
September 2011 report issued by the
team of veterinarians from Denmark, Sweden, Germany, England, and France.

The progression of mitral valve disease can be rapid or slow. In most CKCSs, the disease shows a gradual progression in the loudness of
the murmur and to more serious symptoms, in as little as two years after
first detecting the murmur. But, some
cavaliers develop a mild murmur without any more serious symptoms for many
years. During this period, the dog's heart is doing its best to compensate
for the affects of the blood backflowing through the valve. However, as
veterinary cardiologist Dr. Stephen Ettinger has observed about the dog's
efforts to compensate for those deliterious affects:

"A common characteristic of all compensatory responses is that the
short-term effects are helpful, but the long-term effects are
deleterious."

If the progression is slow enough, the dogs may die of other causes
before their hearts reach failure. This is the usual pattern of MVD in most
other breeds affected with it.

Once the dog reaches the stage of congestive heart failure
(CHF), the average time
until death is nine months.

In the cavalier King Charles spaniel, some cardiologists have found
prognostic value from the degree of mitral valve prolapse, the thickness of
the leaflets, and whether ruptured tendinous chords are observed on the
echocardiogram. In an April 2010
research article, Swedish cardiologists reported finding that cavaliers'
left heart chambers increased in size rapidly only during the last year
before the onset of heart failure. (The x-ray below shows
severe enlargement of the heart, particularly the left side, where the
mitral valve is located.)

Drugs may help to minimize the symptoms, but
eventually the drugs may be unable to control them. Severe symptoms in some
cavaliers will appear more quickly, although previously having been stable.
If the tendinous chords rupture, and the valve leaflets cannot continue to
open and close with each heart beat, death could be almost immediate.

A method which cavalier owners can use to determine if
and when their dog reaches the stage of heart failure is to count
the dog's breaths per minute while sleeping. In
an October 2012 study, researchers found that healthy adult dogs
generally have a mean sleeping respiratory rate of less than 30 breaths per
minute and rarely exceed that rate at any time. Some cardiologists recommend
that their patient's owners periodically count their dog's respiratory rate,
and when the average rate starts to creep up to the high twenties, to make
an appointment for the dog to be re-examined by the cardiologist to see if
the dog is approaching or has reached the stage of heart failure.

Studies are being conducted into possibly slowing the
progression of MVD. These studies, discussed in greater depth below at
Drugs to Slow the
Progression of MVD, involve the testing of medications.

In
a very important 2009 "Consensus
Statement" published by a panel of the board certified veterinary
cardiologists (C. Atkins (left), J.
Bonagura, S. Ettinger, P. Fox, S. Gordon, J. Häggström, R. Hamlin, B. Keene,
V. Luis-Fuentes, and R. Stepien) of the American College of Veterinary Internal Medicine (ACVIM), they create a new classification of stages of
MVD.

They state:

"The new system describes 4 basic stages of
heart disease and failure:

Stage A
identifies patients at high risk for developing heart disease but that
currently have no identifiable structural disorder of the heart (e.g., every
Cavalier King Charles Spaniel without a heart murmur).

Stage B identifies patients with structural
heart disease (e.g., the typical murmur of mitral valve regurgitation is
present), but that have never developed clinical signs caused by heart
failure. Because of important clinical implications for prognosis and
treatment, the panel further subdivided Stage B into Stage B1 and B2.

Stage B1 refers to asymptomatic patients that
have no radiographic or echocardiographic evidence of cardiac remodeling
[enlargement] in
response to CVHD.

Stage B2 refers to asymptomatic patients that
have hemodynamically significant valve regurgitation, as evidenced by
radiographic or echocardiographic findings of left-sided heart enlargement.

Stage C denotes patients with past or current
clinical signs of heart failure associated with structural heart disease.
Because of important treatment differences between dogs with acute heart
failure requiring hospital care and those with heart failure that can be
treated on an outpatient basis, these issues have been addressed separately
by the panel. Some animals presenting with heart failure for the 1st time
may have severe clinical signs requiring aggressive therapy (eg, with
additional afterload reducers or temporary ventilatory assistance) that more
typically would be reserved for those with refractory disease (see Stage D).

Stage D refers to patients with end-stage
disease with clinical signs of heart failure caused by CVHD that are
refractory to 'standard therapy' (defined later in this document). Such
patients require advanced or specialized
treatment strategies in order to
remain clinically comfortable with their disease. As with Stage C, the panel
has distinguished between animals in Stage D that require acute,
hospital-based therapy and those that can be managed as outpatients."

It is unrealistic to try to cure canine mitral valve
disease. "Management" is a word frequently used by veterinary cardiologists
to describe the conventional means of treating MVD. It involves medications,
supplements, and diets intended to compensate for the progression and
symptoms of MVD, especially once the disease reaches heart
failure (HF). The veterinarian tries to eliminate or reduce signs of
fluid accumulation and congestion, and to maintain adequate cardiac output
in order to provide needed blood flow. The degree of treatment will depend
upon the stage of the disease. Early MVD is not treated in the same way as
advanced MVD. The particular management treatments are discussed below: Stage B1
(mild), Stage B2 (moderate),
Stage C (severe), or Stage D
(end stage).

Replacement of the defective mitral valve is available in
veterinary medicine. For example, Colorado State University's James L. Voss
Veterinary Teaching Hospital has such a surgical program under the direction
of Dr. E. Christopher Orton, whose cardiac surgery team has been replacing
canines' heart valves since 1997. (See
Surgery below for more information about various surgical
techniques being used on dogs' mitral valves.) However, surgical replacement usually
is cost-prohibitive and would
require that the dog's renal system and other vital organs be in ideal
condition. Therefore, MVD typically is treated by managing heart failure.
The goals of the veterinary cardiologist are to improve the dog's quality of
life and to increase the length of its life.

Also, in 2008 in at least
one pre-med research paper, the author suggests that injecting bone
marrow stromal cells into the heart of a cavalier King Charles spaniel may
stimulate stem cells to regenerate heart muscle and repair damage to the
valve tissues.

Research in cardiac stem cell therapy is in early stages and is
on-going. Researchers are dealing with issues such as the ever-pumping
heart washing out stem cells which have been inserted into it. In
a 2014 report, veterinary researchers at North Carolina State
University have successfully figured out a way to magnetize cardiac stem
cells so that they are directed to the hearts of rats and remain there
to perform therapeutic effects. The team have attached metalic
nanoparticles from an FDA-approved drug, Feraheme, to cardiac stem cells
and used a magnetic field to keep the cells in the heart. The process
has resulted in a three-fold increase in cell retention in the rats'
hearts.

In
a 2014 Italian doctoral thesis, the researcher suggested that MVD
appears to be associated with a chronic state of inflammation, as
evidenced by measurements of immunoglobulin antibodies and glycoprotein
and complement proteins particularly associated with immune responses to
inflammation. Therefore, among the treatments to consider would be
methods of reducing inflammation by diets and supplements.

A cavalier with early mitral valve disease has a mild murmur
(usually at Grade 1 or 2 out of 6) but
the heart is not enlarged and the dog is symptom-free (asymptomatic). This dog would be at Stage B1 of
the ACVIM's 2009
Consensus Statement,
although a dog with even a higher grade murmur (Grade 3 or 4) could meet the
Stage B1 definition, as long as it is symptom-less and has no heart enlargement. Cardiologists refer to this as the
pre-clinical stage. At this stage, there is no need for treatment*,
but heart size should be monitored by x-rays every 6 to 12 months.
Overweight dogs should be put on a weight-reducing diet. Low salt diets have
been suggested, to help reduce water retention. It would be prudent to avoid
extreme exertion.

* The
participating cardiologists in the ACVIM's 2009
Consensus
Statement unanimously declined to recommend any drug or dietary therapy
for Stage B1 dogs.

"Treatment of the asymptomatic dog with a murmur caused
by endocardiosis is not currently recommended unless there is evidence of
impending heart failure (dramatic cardiomegaly and pulmonary venous
distension). Scandinavian studies in the CKCS dog have failed to reveal any
benefit in asymptomatic dogs; results from a North American study suggest a
possible benefit, but were by no means conclusive."

• Flavonex,
a salvia and gingko extract herbal supplement made by Health Concern.

• (Natural supplements which may help to strengthen and
energize the heart of a dog with severe MVD include D-Ribose
(Corvalen
Riboseor
Pure Encapsulations Ribose),
also known as alpha-D-ribofuranoside, which reportedly
improves ventilatory efficiency in patients with heart failure
(HF). See 2009 report. It also
reportedly boosts the energy level of heart muscle cells, improving
cardiovascular function and the flow of blood.)

Vitamins and food supplements
such as these may be prescribed for all stages of mitral valve disease.
Holistic supplements should be taken only if prescribed by a licensed
veterinarian who also is holistically trained. A search webpage for
finding holistic veterinarians in the United States is locatedhere .

If cavalier owners choose to ignore this advice to consult with an
holistic veterinarian before giving their dogs supplements, they
nevertheless should be aware of falsehoods about certain supplements,
such as taurine. Research studies have shown that
MVD-affected dogs tend to have higher plasma taurine
concentrations than unaffected dogs. In
a 1995 study (by George A. Kramer, Mark D. Kittleson, Philip R. Fox,
Julia Lewis, and Paul D. Pion), for example, "[P]lasma taurine
concentrations were highest in dogs with AVD [acquired valvular disease,
e.g, MVD] ... We conclude that plasma taurine concentrations may be
increased in dogs with AVD." In
a 2002 presentation, Dr. Bruce Keene stated: "Taurine
supplementation is indicated whenever plasma or whole blood taurine
concentrations are found to be low. ... [S]upplementation is generally
only recommended after discovery of deficiency." See, also, Dr.
Rebecca E. Gompf's
2005 article on nutritional therapies.

The participating cardiologists
in the ACVIM's 2009 Consensus
Statementunanimously declined to recommend any drug or dietary therapy
for Stage B1 dogs. Nevertheless, studies of drugs have been conducted on
dogs in Stage B1, and what follows is a discussion of the reports of those
studies:

Angiotensin
converting enzyme inhibitors (ACE-inhibitors or ACE-I) in humans
have been found to widen blood vessels by relaxing the smooth muscle cells
in the vessels' walls (vasodilation), counteract fluid retention, and blunt
heart enlargement due to MVD. However, in dogs with Stage B1 MVD, the
results have been more mixed and less favorable.

As noted, the ACVIM
Consensus
Statement does not recommend ACE-inhibitors for Stage B1 (or Stage B2)
dogs. This is because they have never been approved for veterinary medicine
for MVD dogs in Stage B1 (or Stage B2) by regulating authorities. They
have been approved only for MVD dogs in heart failure (HF) --
Stage C -- when combined with other therapies, such as diuretics. The
reason for not prescribing ACE-inhibitors prior to heart failure (HF) is obvious: A
2002 Scandinavian study
(the "Scandinavian Veterinary Enalapril Prevention [SVEP] Trial")
of 229 asymptomatic cavalier King Charles spaniels with mild MVD murmurs
(therefore, at Stage B1) has shown that ACE-inhibitors had no
significant affectupon the time from the initiation of ACE-I
therapy to the point of heart failure. A
2007 study
(the "VETPROOF Trial"), sponsored by a drug manufacturer and involving 124
dogs of several breeds (including only 10 cavaliers), showed that enalapril
given to dogs with only mild MVD murmurs and some enlargement of the heart
but which otherwise are symptomless, "modestly delayed" the onset of HF.
(Also, see below for discussion of ACE-inhibitors'
adverse side effects.)

This chart, prepared by veterinary cardiologist Dr.
Niek Beijerink, compares the results of the two ACE-inhibitor studies. The
2002 SVEP study of only cavaliers is summarized on the left, and the 2007
VETPROOF study is on the right. He concluded from these results that no
ACE-inhibitors should be given prior to heart failure --
Stage C (see
below).

Because ACE-inhibitors have the potential to adversely affect renal
function, a baseline renal panel should be conducted before treatment
was initiated and again three to five days later. Adverse reactions to
the drug typically occur within three to five days of therapy
initiation.

--- natural alternatives to ACE-inhibitors

A natural supplement as an alternative to ACE-inhibitors is a
combination of active fish petides, including LKPNM, from the bonito fish (Sarda
orientalis), such as Vasotensin, manufactured by Metagenics,
Inc., and
PeptACE by Natural Factors. Holistic supplements should be taken only if prescribed by a
licensed veterinarian who also is holistically trained in TCM. Search
webpages for finding holistic veterinarians in the United States are located here
and here.

Other Chinese herbal alternatives include Salvia
Shou Wu, a Seven Forests patented supplement which consists of
Salvia extract, and several other herbs and flowers. Salvia Shou Wu
encourages blood circulation.

--- alpha & beta blockers in Stage B1

As noted, the ACVIM
Consensus
Statement does not recommend any drugs for Stage B1 dogs.
Nevertheless, other drugs being used by some veterinary cardiologists are carvedilol (Coreg),
and bisoprolol, both non-selective beta-and alpha-blockers with anti-oxidant
effects which reduce the heart's rate and the force of its contraction,
thereby reducing the work of the heart. Carvedilol and bisoprolol also cause
the arteries to relax and the blood pressure to drop. A few cardiologists
have begun to administer low doses of carvedilol and Bisoprolol early in the
disease process, in hopes of causing MVD to progress at a slower rate
than dogs not taking the medication. A less expensive alternative
beta-blocker is atenolol (Tenormin, Tenoretic). However, atenolol lacks the
vasodilatory and antioxidant properties of carvedilol.

Cardiologists often refer to these drugs as beta- (β-)
adrenergic receptor antagonists (BARA).

--- pimobendan in Stage B1

Finally, pimobendan (Vetmedin,
Cardisure), which has been
prescribed for dogs in heart failure, is
the subject to research for treatment of dogs in the early stage of MVD. In
October 2010, cardiologists worldwide began a five-year study (the "EPIC Trial") giving pimobendan to cavaliers with low grade MVD murmurs to see if the drug will
slow the progression of MVD to heart failure. However, research
reports are conflicting, and harmful side effects have been noted from early
use of this drug. See the "A Few Words About Pimobendan" box
below for details. As noted above, the members of the ACVIM panel who
participated in its 2009
Consensus Statementunanimously refused to recommend prescribing pimobendan to Stage B1 dogs.

Moderate
MVD is indicated by a louder murmur and some
enlargement of the heart on x-rays or scan. At this stage, reducing exercise will help to reduce the heart's
workload. This is a Stage B2 dog, according to the 2009 ACVIM
Consensus Statement.

A majority of the participating cardiologists in the ACVIM's 2009
Consensus
Statement declined to recommend any drug or dietary therapy
for Stage B2 dogs, apart from an ACE-inhibitor. Nevertheless, some cardiologists begin prescribing
other
medications at this stage, and studies of drugs have been conducted on dogs
in Stage B2. What follows is a discussion of the reports of those studies.

--- diuretics

Loop diuretics (furosemide[such as Lasix, Diuride, Frudix, Frusemide,
Salix],
hydrochlorothiazide [Dyazide, Thiuretic, Esidrix, Hydrodiuril], and co-amilozide, a
combination of amiloride and hydrochlorothiazide), which are drugs which cause the kidneys to
excrete more fluid than normal, may be used to remove excess fluid from the
blood system.
Furosemide reduces the total circulating blood volume, which in turn reduces
pressure in the left atrial and left ventricle chambers of the heart.
Side effects would be that the dog is thirstier than normal, and increased
urination.

Furosemide can severely affect the kidney by activating the
renin-angiotensin aldosterone system (RAAS), since reduction in the total
circulating blood volume results in activation of RAAS. Furosemide also can
adversely affect the liver and other bodily
functions, and so a baseline of the kidneys and liver should be evaluated before starting furosemide and should be monitored
three to five days later (since adverse reactions to the drug typically
occur within three to five days of therapy initiation) and every three months thereafter.

In a
2009 study report which did not include CKCSs, veterinary cardiologists
observed a three-fold increase in RAAS activity using furosemide.
Their conclusion was that "furosemide is not recommended for chronic use in
the absence of concurrent therapy to blunt RAAS activity, such as ACE-I, aldosterone receptor blockers, or angiotensin II type I receptor blockers." A
subsequent similar study in 2011 concluded:

"These results in clinically normal dogs suggested that furosemide, administered with or without pimobendan, should be accompanied by RAAS-suppressive treatment."

Aldosterone receptor blockers include Losartan potassium (Cozaar).

Medications approved to treat humans with heart failure, such
as the aquaretic (vasopressin receptor anatagonist = vaptans), (tolvaptan),
and another loop diuretic, torsemide (Demadex), are being
empirically considered as alternatives to diuretics such as furosemide. In a
2012 report, researchers
compared doses of torsemide and furosemide in treating dogs with stable
heart failure (Stage C). They found that "torsemide is equivalent
to furosemide at controlling clinical signs of CHF in dogs and is likely to
achieve greater diuresis vs. furosemide." Torsemide is approximately
10-times as potent as furosemide
in dogs and cats.

Carperitide, an alpha-human atrial natriuretic peptide,
is a human drug which is known to reduce pressure in the left atrial and
left ventricle chambers of the human heart. In an
August
2013 report, a team of Japanese veterinary heart surgeons compared
dosing lab dogs with carperitide and furosemide. The team reported that both
drugs similarly reduced left atrial pressure. They found that carperitide
had less adverse effects than furosemide because it did not activate the
renin–angiotensin–aldosterone system (RAAS). They concluded that additional
studies are warranted in clinical patients with degenerative MVD and
congestive heart failure.

--- natural alternative diuretics

Natural diuretics include urea (AC Carbamide) by
Standard Process, and Wu Ling San
by Mayway and Alisma
by Seven Forests, both traditional Chinese herbal medicines (TCM). Holistic
supplements should be taken only if prescribed by a licensed veterinarian
who also is holistically trained in TCM. Search
webpages for finding
holistic veterinarians in the United States and Canada are located here
and here,
and in the United Kingdom,
here.

--- ACE-inhibitors in Stage B2

ACE-inhibitors (enalapril maleate [Enacard, Vasotec, Prilenal], benazepril [Lotensin,
Fortekor, Benefortin, VetACE], imidapril [Tanatril], ramipril [Altace, Tritace, Vasotop]),
captopril, lisinopril, may also be prescribed by some
cardiologists. As stated in more
detail in the Stage B1 discussion above, ACE-inhibitors block the angiotensin
converting enzyme, which is necessary to produce a substance that causes
blood vessels to tighten. So, ACE-I serve to relax the blood vessels,
thereby lowering the blood pressure and increasing the supply of blood and
oxygen to the heart. However, studies have shown only a low concentration of
angiotensin II receptors in dogs' affected mitral valves. Therefore, the
ACVIM
Consensus Statement
has not endorsed ACE-I therapy of MVD dogs at Stage B2 MVD. Further, ACE-Is
have not been approved for veterinary medicine for MVD dogs in Stage B2 by
regulating authorities. However, a majority of the ten members of the ACVIM
Consensus Statement panel did recommend starting an ACE-inhibitor at Stage
B2 (although their reasoning was not included in the Consensus Statement).

An additional reason for not prescribing ACE-inhibitors prior to
heart failure is a
2002 Scandinavian study
(the "Scandinavian Veterinary Enalapril Prevention [SVEP] Trial")
of 229 asymptomatic cavalier King Charles spaniels with mild MVD murmurs,
which has has shown that ACE-inhibitors had no significant
affectupon the time from the initiation of ACE-I therapy to
the point of heart failure (HF). A
2007 study
(the "VETPROOF Trial"), sponsored by a drug manufacturer and involving 124
dogs of several breeds (including only 10 cavaliers), showed that enalapril
given to dogs with only mild MVD murmurs and some enlargement of the heart
but which otherwise are symptomless, "modestly delayed" the onset of HF.
(Also, see below for discussion of ACE-inhibitors'
adverse side effects.) Further, in a
2013 study by Thai
graduate students, of twenty dogs (none CKCS) in Stage B2, they found that
ramipril did not affect cardiac chamber size, mitral regurgitation severity
and systolic function assessed by echocardiography in 91-day period of
treatment.

This chart, prepared by veterinary cardiologist Dr.
Niek Beijerink, compares the results of the two ACE-inhibitor studies. The
2002 SVEP study of only cavaliers is summarized on the left, and the 2007
VETPROOF study is on the right. He concluded from these results that no
ACE-inhibitors should be given prior to heart failure --
Stage C (see
below). Other researcher-cardiologists, including Drs. Mark Oyama and
Adrian Boswood, have reached the same conclusion that ACE-Is at Stage B2
is not appropriate. In a 2012 presentation, Dr. Oyama stated that not
giving an ACE-inhibitor to Stage B2 cavalier King Charles spaniels was
"a slam dunk" decision, in view of the SVEP trial of 229 cavaliers,
noted above.

Nevertheless, Dr. John Bongura reported in 2010 that out of 100 board
certified veterinary cardiologists surveyed, nearly 70% indicated that
an ACE-inhibitor was warranted for dogs in Stage B2, notwithstanding the
lack of any research reports supporting their conclusions.

Recent studies have concluded that diuretics such as furosemide
should be used only combined with ACE-inhibitors -- which also prevent fluid
retention -- so that the diuretic dosage may be sharply reduced to avoid the
worst of its negative side effects, such as activation of the
renin-angiotensin aldosterone system (RAAS), a cause of renal dysfunction.

In studies, ACE-inhibitor enalapril has improved survival
by more than 100%, and reduced pulmonary edema and improved quality of life
scores, for dogs in congestive heart failure (CHF). Studies also found that exercise capacity was also improved in dogs
with experimental mitral regurgitation. Benazepril also has been shown to
improve survival, and imidapril was shown to be equal to enalapril in
survival studies of dogs in heart failure due to mitral regurgitation.

However, ACE-inhibitors may have serious side effects. They can cause severe renal
insufficiency, and the kidneys should be monitored carefully when using
these drugs. A baseline renal panel should be conducted before treatment is
initiated and again five to ten days later. Adverse reactions to the drug
typically occur within three to five days of therapy initiation.

Benazepril (Lotensin, Fortekor, Benefortin, VetACE) is reported to be slightly less
harsh on the kidneys than is enalapril maleate (Enacard, Vasotec) or
ramipril (Altace, Tritace, Vasotop). Also, ACE-inhibitors traditionally are used for the treatment of high blood pressure.
However, not all veterinary cardiologists check a cavalier's blood pressure
before prescribing the drug. Unless the dog's blood pressure is high, the
use of an ACE-inhibiting drug could dangerously lower its blood pressure.

The use of ACE inhibitors combined with extreme salt (sodium) restriction
may contribute to renal dysfunction by activating the renin-angiotensin
aldosterone system (RAAS). Therefore, some cardiologists recommend only
moderate salt restricted diets when prescribing ACE inhibitors.

Other side effects include the accumulation of toxins which can damage
the liver, anorexia or loss of appetite, vomiting, azotemia -- elevation of
blood urea nitrogen (BUN) -- and the
development of a dry cough due to the accumulation of bradykinin. Since a
dry, hacking cough is a frequent symptom of progressing MVD, this side
effect of the drug could be confused with the worsening of the disease.

Researchers have found that extensive use of diuretics alone may contribute
to renal dysfunction by activating the renin-angiotensin aldosterone system
(RAAS) , as well as dehydration, azotemia (elevation of blood urea nitrogen
[BUN]), and hypokalemia (low potassium). However, in a
September 2014 study of ten healthy hounds, researchers found that
benazepril did not prevent the activation of the renin-angiotensin
aldosterone system (RAAS), a cause of renal dysfunction.

A baseline renal panel should be conducted before treatment
is initiated and again three to five days later. Adverse reactions to
the drug typically occur within three to five days of therapy
initiation.

--- natural alternatives to ACE-inhibitors

A natural supplement as an alternative to ACE-inhibitors is a
combination of active fish petides, including LKPNM, from the bonito fish (Sarda
orientalis), such as Vasotensin, manufactured by Metagenics,
Inc., and
PeptACE by Natural Factors. Holistic supplements should
be taken only if prescribed by a licensed veterinarian who also is
holistically trained in TCM. Search webpages for finding holistic
veterinarians in the United States and Canada are located here
and here,
and in the United Kingdom,
here..

Other Chinese herbal alternatives include Salvia
Shou Wu, a Seven Forests patented supplement which consists of
Salvia extract, and several other herbs and flowers. Salvia Shou Wu
encourages blood circulation.

--- aldosterone antagonist in Stage B2

Spironolactone (Aldactone,
Prilactone), an aldosterone antagonist (or mineralocorticoid
receptor blocker -- MRB), is known as a potassium-sparing diuretic. In a 2010 European
study, spironolactone, when added to conventional
cardiac therapy (such as an ACE-inhibitor, plus furosemide and digoxin if
needed) decreases the risk of reaching the primary endpoint (ie,
cardiac-related death, euthanasia, or severe worsening) in dogs with
moderate to severe mitral regurgitation caused by MVD.*

*But see a
2011 report
indicating that spironolactone did not extend survival times of dogs with
advanced heart failure.

Spironolactone has been approved within the European Union for use in
dogs with clinical signs of HF secondary to MVD (meaning, Stage C MVD), as adjunctive therapy. It
typically acts as a comparatively weak diuretic, when
administered alone, but has synergistic effects when combined with other
diuretics. The main reason for prescribing it is to protect the dog against
the harmful effects of aldosterone on the heart and blood vessels.

However, spironolactone, which is known as a potassium-sparing diuretic because, unlike some other
diuretics, it does not cause the loss of potassium -- reportedly may lead to
excessively high, life-threatening levels of potassium in the dog's blood,
particularly when combined with ACE inhibitors. Some veterinary
cardiologists recommend that potassium levels be carefully monitored when
using spironolactone in combination with ACE inhibitors by drawing blood at
regular intervals until it is evident that the potassium level is or is not
going to be a problem.

In a
2013 study of the possible increased risk of adverse events for dogs
taking spironolactone in addition to conventional therapies, the researchers
concluded that dogs with heart failure receiving spironolactone in addition
to conventional treatment are not at a higher risk for any adverse events,
death caused by cardiac disease, renal disease, or both, hyperkalemia, or
azotemia. The study was funded by the manufacturer of Prilactone.

Cardalis is a tablet which combines
spironolactone with the ACE-inhibitor benazepril. Aldactazide
is a combination of spironolactone and hydrochlorothiazide, which
inhibits the activity of the hormone aldosterone.

In 2010, a team of Italian cardiologists, led by
Dr. Michele
Borgarelli, began the DELAY Study of 240 dogs to determine if giving
combined doses of spironolactone and benazipril can delay the
onset of symptoms of heart failure in dogs with MVD. The study is
scheduled to end in December 2015.

--- alpha & beta blockers

Carvedilol (Coreg), and bisoprolol, also are being prescribed for
Stage B2 MVD by some cardiologists. They are non-selective beta-and alpha-blockers with
anti-oxidant effects -- also known as beta- (β-)
adrenergic receptor antagonists (BARA) -- which reduce the heart's rate and the force of its
contraction, thereby reducing the work of the heart. Also, in
a 2009 study, it has been
suggested that BARA have the potential to slow the progression of the mitral
valve's degeneration by interfering with the serotonin signaling pathway --
a possible major factor in MVD progression -- and by reducing the "wear and
tear" of the valve by reducing the pressure differences between the left
ventricle and atrium. In a
2012 report, researchers
studied the effect of carvedilol in treating cavaliers with Stage B2 MVD and
found no adverse effects and median survival of 48.5 months.

Other beta blockers include metoprolol
(Lopressor, Toprol).

--- pimobendan in Stage B2

A majority of the ACVIM panel who participated in its 2009
Consensus Statementdid not recommend prescribing pimobendan (Vetmedin,
Cardisure)
to Stage
B2 dogs. The U.S. Food and Drug Administration’s (FDA)
2007 report approving the use of pimobendan for dogs also contains the
warning that the drug not be prescribed by dogs which are not
in heart failure. On each container of Vetmedin is the warning
that “Vetmedin should not be given in cases ... where an augmentation of
cardiac output is inappropriate for functional or anatomical reasons.
Warnings: Only for use in dogs with clinical evidence of heart failure.” See
the "A Few Words About Pimobendan" box below for
details.

Severe MVD normally involves a murmur that has become much louder.
However, the murmur can become more difficult to hear, if the heart's
deterioration has been sudden. So a Grade 6 murmur later could be downgraded
to a Grade 5, but that would not mean an improvement in the dog's condition.
Also, the dog likely will have some "clinical signs" of heart failure, such
as difficulty breathing while at rest, and may not be
able to tolerate even minimal exercise. This is a Stage C dog, according to
the 2009 ACVIM
Consensus Statement.
Most MVD-affected dogs at Stage C are in congestive heart failure (CHF), a
common term used by cardiologists to describe dogs with pulmonary congestion
and edema.

Cardiologists categorize "clinical signs" of heart failure as either
"congestive", meaning the production of fluids which may enter the
pulmonary vein and the lungs, or "low output", meaning that the heart is
not pumping adequately to energize the dog's body. Here is a chart from
Dr. Beardow's presentation
showing the two classifications of clinical signs:

A method which cavalier owners can use to
determine if and when their dog reaches the stage of heart
failure is to count the dog's breaths per minute while sleeping. See our
section above on Respiratory Rates for
details. In
an October 2012 study, researchers found that healthy adult dogs
generally have a mean sleeping respiratory rate of less than 30 breaths
per minute and rarely exceed that rate at any time. Some cardiologists
recommend that their patient's owners periodically count their dog's
respiratory rate, and when the average rate starts to creep up to the
high twenties, to make an appointment for the dog to be re-examined by
the cardiologist to see if the dog is approaching or has reached the
stage of heart failure.

Dogs in HF with clinical signs mild enough for home
therapy are classified as in Stage Cc ("c" for "chronic"). Pressure in the left atrium can be
relieved by diuretics* and drugs which lower the pressure in the veins,
called venodilators. Diuretics should be given by injection in severe cases.
ACE-inhibitors also have venodilating effects.

* See
diuretics above. In a
2012
report, researchers compared doses of torsemide and furosemide in
treating dogs with stable heart failure (Stage C). They found
that "torsemide is equivalent to furosemide at controlling clinical signs of
CHF in dogs and is likely to achieve greater diuresis vs. furosemide."

--- diuretics in Stage C

Treatment will be necessary at Stage C, usually in a tablet
form. Since a dog with moderate MVD begins to retain fluid and salt, drugs
which prevent fluid retention, or which increase fluid elimination, may be
used. Loop diuretics (furosemide[such as Lasix, Diuride, Frudix, Frusemide,
Salix],
hydrochlorothiazide [Dyazide, Thiuretic, Esidrix, Hydrodiuril], and co-amilozide
or amiloride/hydrochlorothiazide (Moduretic) , a
combination of amiloride and hydrochlorothiazide),
which are drugs which cause the kidneys to excrete more fluid than normal,
may be used to remove fluid from the lungs. Side effects would be that the
dog is thirstier than normal, and increased urination. Furosemide can
severely affect the kidney by activating the renin-angiotensin aldosterone
system (RAAS), as well as the liver and other bodily functions, and so a
baseline of the kidneys and liver should be evaluated before starting
furosemide and should be monitored three to five days later (since adverse
reactions to the drug typically occur within three to five days of therapy
initiation) and every three months thereafter.

In a
2009 study report which did not include CKCSs, veterinary cardiologists
observed a three-fold increase in RAAS activity using furosemide.
Their conclusion was that "furosemide is not recommended for chronic use in
the absence of concurrent therapy to blunt RAAS activity, such as ACE-I, aldosterone receptor blockers, or angiotensin II type I receptor blockers." A
subsequent similar study in 2011 concluded:

"These results in clinically normal dogs suggested that furosemide, administered with or without pimobendan, should be accompanied by RAAS-suppressive treatment."

Aldosterone receptor blockers include Losartan potassium
(Cozaar).

Medications approved to treat humans with congestive heart failure, such
as the aquaretic (vasopressin receptor anatagonist = vaptans), (tolvaptan),
and another loop diuretic, torsemide (Demadex), are being
empirically considered as alternatives to diuretics such as furosemide. In a
2012 report, researchers
compared doses of torsemide and furosemide in treating dogs with stable
congestive heart failure (Stage C). They found that "torsemide is equivalent
to furosemide at controlling clinical signs of CHF in dogs and is likely to
achieve greater diuresis vs. furosemide." Torsemide is approximately
10-times as potent as furosemide
in dogs and cats.

--- natural alternative diuretics

Natural diuretics include urea (AC Carbamide) by
Standard Process, and Wu Ling San
by Mayway and Alisma
by Seven Forests, both traditional Chinese herbal medicines (TCM). Holistic
supplements should be taken only if prescribed by a licensed veterinarian
who also is holistically trained in TCM. Search
webpages for finding
holistic veterinarians in the United States are located here
and here.

--- ACE-inhibitors in Stage C

ACE-inhibitors (enalapril maleate [Enacard, Vasotec, Prilenal], benazepril [Lotensin,
Fortekor, Benefortin, VetACE], imidapril [Tanatril], ramipril [Altace, Tritace, Vasotop]),
captopril, lisinopril, usually also will be prescribed. ACE inhibitors block the angiotensin converting enzyme, which is necessary to produce a substance
that causes blood vessels to tighten. So, ACE inhibitors serve to relax the
blood vessels, thereby lowering the blood pressure and increasing the supply
of blood and oxygen to the heart. The result is that in dogs in heart failure (HF), they tend to blunt the
enlargement of the heart and slow the progression of heart failure.

Recent studies have concluded that diuretics such as furosemide
should be used only combined with ACE inhibitors -- which also prevent fluid
retention -- so that the diuretic dosage may be sharply reduced to avoid the
worst of its negative side effects. Researchers have found that extensive use of diuretics alone may contribute
to renal dysfunction by activating the renin-angiotensin aldosterone system
(RAAS) , as well as dehydration, azotemia (elevation of blood urea nitrogen
[BUN]), and hypokalemia (low potassium).

However, in a
September 2014 study of ten healthy hounds, researchers found that
benazepril did not prevent the activation of the renin-angiotensin
aldosterone system (RAAS), a cause of renal dysfunction.

A natural supplement as an alternative to ACE-inhibitors is a
combination of active fish petides, including LKPNM, from the bonito fish (Sarda
orientalis), such as Vasotensin, manufactured by Metagenics,
Inc., and
PeptACE by Natural Factors. Holistic supplements should be taken only if prescribed by a
licensed veterinarian who also is holistically trained in TCM. Search
webpages for finding holistic veterinarians in the United States are located here
and here.

Other Chinese herbal alternatives include Salvia
Shou Wu, a Seven Forests patented supplement which consists of
Salvia extract, and several other herbs and flowers. Salvia Shou Wu
encourages blood circulation.

LASSBio 897 is a new prototype drug produced from safrole substrate,
a compound extracted from the “sassafras oil”, found in Brazilian plants
like “canela-branca” (Ocotea pretiosa), caused vasodilation
after two hours of their administration, similar to what was observed
with benazepril.

--- spironolactone, aldosterone antagonist in Stage C

Spironolactone (Aldactone,
Prilactone), an aldosterone antagonist (or mineralocorticoid
receptor blocker -- MRB), is known as a potassium-sparing diuretic. In a 2010 European
study, spironolactone, when added to conventional
cardiac therapy (such as an ACE-inhibitor, plus furosemide and digoxin if
needed) decreases the risk of reaching the primary endpoint (ie,
cardiac-related death, euthanasia, or severe worsening) in dogs with
moderate to severe mitral regurgitation caused by MVD.*

*But see a
2011 report
indicating that spironolactone did not extend survival times of dogs with
advanced heart failure.

Spironolactone has been approved within the European Union for use in
dogs with clinical signs of HF secondary to MVD, as adjunctive therapy. It
typically acts as a comparatively weak diuretic, when
administered alone, but has synergistic effects when combined with other
diuretics. The main reason for prescribing it is to protect the dog against
the harmful effects of aldosterone on the heart and blood vessels.

However, spironolactone, which is known as a potassium-sparing diuretic because, unlike some other
diuretics, it does not cause the loss of potassium -- reportedly may lead to
excessively high, life-threatening levels of potassium in the dog's blood,
particularly when combined with ACE inhibitors. Some veterinary
cardiologists recommend that potassium levels be carefully monitored when
using spironolactone in combination with ACE inhibitors by drawing blood at
regular intervals until it is evident that the potassium level is or is not
going to be a problem.

Cardalis is a tablet which combines
spironolactone with the ACE-inhibitor benazepril. Aldactazide
is a combination of spironolactone and hydrochlorothiazide, which
inhibits the activity of the hormone aldosterone.

--- pimobendan & arteriolardilators in Stage C

Reducing pressure in the arteries can make it easier for the heart to
pump. ACE-inhibitors reduce arterial pressure, as do the arteriolardilators
hydrazaline (Apresoline), pimobendan (Vetmedin, Cardisure),
milrinone (Primacor), levosimendan (Simdax), SCH00013,and sodium nitroprusside. In advanced heart failure,
the heart muscle may become weakened so that it does not contract properly.
Digoxin (Lanoxin), a cardiac glycoside extracted from the foxglove plant
(digitalis), may be used to improve heart muscle strength to help the heart
contract more strongly. Pimobendan (Vetmedin,
Cardisure) reportedly eases the
resistance in the circulatory system by dilating blood vessels, and improves
the efficiency with which the heart can function as a pump, thereby both
improving cardiovascular function and the blood flow to major organs.

--- hypertension (high blood pressure) medications

Sildenafil (Viagra, Revatio) (a/k/a sildenifil) a phosphodiesterase (PDI) 5
inhibitor, is being prescribed to lower pulmonary hypertension by some
cardiologists for dogs with congestive heart failure, often in
combination with pimobendan. In an
April 2006 French study report,
tadalafil
(Cialis), a long-acting PDI-5 inhibitor, belonging to the same family as
sildenafil, has been shown to have decreased systolic pulmonary arterial
pressure significantly. Another such pde-5 inhibitor is varenafil (Levitra).
However, in
a March 2012 article, researchers opined that "further studies are
required to delineate the clinical effects and potential clinical value of
these medications."

To the contrary, research by Dr. Rosemary A Henik, of the
University of Wisconsin-Madison, has indicated that pulmonary venous
hypertension due to left heart disease, is managed best with "afterload"
reduction, and not sildenafil. More recently, a 2007 study by
Drs. Joao S. Orvalho, William P. Thomas,
and P. H. Kass found that "these data suggest
that oral tadalafil, when added to conventional heart failure therapy,
decreases the pulmonary artery pressure in this group of dogs."

Diltiazem (Cardizem, Tiazac) and amlodipine besylate (Norvasc)
are calcium channel
blockers (CCBs) medication used to treat hypertension in dogs. Calcium
channel blockers, also called calcium antagonists, decrease the flow of
calcium into muscle cells. See
this 2012 comparative study of amlodipine versus benazepril. In
a
2011 study, the Canadian researchers concluded that:

"Combining furosemide, ACEI, pimobendan, spironolactone, and
amlodipine may result in long survival times in dogs with MR [mitral
regurgitation] and CHF."

---other medications

Nesiritide (Natrecor), the recombinant form of B-type natriuretic peptide (BNP),
the peptide hormone discussed above, has
been shown in studies of induced severe CHF in dogs, when combined with
the diuretic furosemide, to inhibit activation of aldosterone while
maximizing natriuresis and diuresis and preserving renal function. See,
for example,
this 2004 report.

In addition to the natural alternatives to diuretics and ACE inhibitors
and arteriolardilators
described above, natural supplements which may help to strengthen and
energize the heart of a dog with severe MVD include D-Ribose
(Corvalen
Riboseor
Pure Encapsulations Ribose),
also known as alpha-D-ribofuranoside, which reportedly
improves ventilatory efficiency in patients with congestive heart failure
(CHF). See this
2003 human study report and this
2004
human study report and this 2009 human
study report and this
2010
canine treatment summary report. It also reportedly
boosts the energy level of heart muscle cells, improving cardiovascular
function and the flow of blood. Holistic supplements should be taken
only if prescribed by a licensed veterinarian who also is holistically
trained in TCM. A search webpage for finding holistic veterinarians in the
United States are located here
and here.

A good general health supplement for older dogs in congestive heart
failure is N, N-Dimethylglycine
(DMG). Vetri-DMG is a pure DMG product offered by Vetri-Science Laboratories
of Vermont (www.vetriscience.com). DMG is said to support the immune system,
promote oxygen utilization, improve cardiovascular function, support liver
function, and support ocular health.

--- hospitalization

As
noted above, dogs with severe (acute) signs of HF -- Stage C1 -- require
hospitalization for stabilization. In cases of acute heart failure, the hospitalized dog may also be treated with intravenous injections of diuretics and pimobendan. Oxygen
may be administered by either housing the dog in an oxygen cage
(right) or a
nasal tube, called a cannula. The dog also may be sedated to counter any
anxiety it may be experiencing from its condition.

Some drugs not discussed in any detail here -- such as nitroglycerin ointment, dobutamine, and
hydalazine -- likely also will be administered during
hospitalizations.

-- end stage of MVD (Stage D)

Cavalier King Charles spaniels suffering from mitral
valve disease (MVD) received a dose of really good news in April 2007, when
the U.S. Food and Drug Administration approved the use of pimobendan to
treat dogs suffering from heart failure (HF), a particularly
common disorder in cavaliers. (See
FDA Approval Report.)

Pimobendan (Vetmedin,
Cardisure) has been shown to improve the
quality of life for dogs suffering from CHF due to MVD. Pimobendan is a benzimidazole pyridazinone derivative and is classified as an inodilator (a
calcium sensitizer and phosphodiesterase-III inhibitor and a positive inotrope and arteriovenous dilator) which reportedly eases the resistance in
the circulatory system by dilating blood vessels. Other inodilators
are milrinone, levosimendan, and SCH00013.

Often, the cavalier in the late stage of heart
failure suffers from a progressive deterioration of the quality of its life,
which is due to the combination of an inability to comfortably keep the dog
free from fluid congestion in its heart, lungs, and abdominal cavity,
together with enlarged heart chambers, lethargy, collapse, and deterioration
of its kidney and/or liver functions. Eventually diuretics, ACE inhibitors,
and other drugs no longer are able to remove enough of the fluids and
increase the supplies of blood and oxygen to the heart. At that point, often
the owner elects euthanasia, rather than to allow the dog to continue to
suffer.

Pimobendan now may be called to the rescue. In addition
to dilating the blood vessels like ACE inhibitors do, pimobendan increases
the strength with which the heart muscle contracts, which improves the
heart’s efficiency to function as a pump, and increases the blood flow to
major organs. It even has been shown, in some studies, to actually reduce
the amount of backflow of blood through the mitral valve and reverse the
enlargement of the heart chambers. And, it may be administered safely with
diuretics, ACE inhibitors, and digoxin. The FDA report states that
pimobendan "is indicated for use with concurrent therapy for heart failure (e.g., furosemide, etc.) as appropriate on a case-by-case
basis." Furosemide is a diuretic.

Remarkably, pimobendan also has been shown to have fewer severe side
effects than its main rival drugs, the ACE inhibitors benazepril (brand
names Lotensin, Fortekor) and enalapril maleate (brand names Enacard,
Vasotec). See ACE Inhibitors -- More Pluses Or Minuses?

Before prescribing pimobendan, cardiologists may require
an echocardiogram to measure the heart's contractility. This
precautionary test is recommended, because a negative effect
reportedly has been instances of pimobendan improving the heart’s
pumping ability and contractility to the extent that the mitral
valve's major chordae tendineae have been overworked and have
actually ruptured, causing immediate death. Therefore, the drug
should not be prescribed for dogs whose hearts have remained strong
despite the MVD. Cavalier owners should never self-prescribe pimobendan for their dogs suffering from mitral valve disease.

Owners also should be wary of general practice
veterinarians prescribing pimobendan without first consulting with a
cardiologist about performing an echocardiogram to resolve the
contractility issue. Also, pimobendan should not be prescribed by
a non-cardiologist for CKCSs which are not in heart
failure (HF). Researchers have reported severe adverse
cardiac effects upon pimobendan-treated dogs not in HF, including
increased blood backflow through the valve, heart enlargement, and
deterioration of the chordae tendinae. We have found, now that
pimobendan is available to the general practice veterinarians, that
many of them are prescribing it without taking the precautions which
would be instinctive to cardiologists and internal medicine
specialists.

On the container of Vetmedin tablets,
there is this warning:

"Contraindications:
Vetmedin should not be given in cases of hypertrophic
cardiomyopathy, aortic stenosis, or any other clinical condition
where an augmentation of cardiac output is inappropriate for
functional or anatomical reasons.

Warnings:Only for use in dogs with clinical evidence of heart
failure."

Also, on Vetmedin's website, it has this
warning:

"The safety of VETMEDIN has not been established in dogs
with:

●Asymptomatic
heart disease●Heart
failure caused by etiologies other than atrioventricular valvular
insufficiency or dilated cardiomyopathy●Dogs
younger than 6 months of age●Dogs
with congenital heart defects●Dogs
with diabetes mellitus or other serious metabolic diseases●Dogs
used for breeding or pregnant or lactating bitches."

Pimobendan was developed by Boehringer Ingelheim GmbH, a
German pharmaceutical company, and is marketed under the registered brand
name "Vetmedin". In Europe and elsewhere apart from the United States, it
has been studied since the late 1980s and prescribed by veterinarians since
the 1990s. There, it is offered by EuroVet Animal Health BV, a Netherlands
company, as "Cardisure". Pimobendan can be expensive. It has become a popular item on the
underground drug market and on international Internet websites. Overseas
shipments reportedly had been delayed by U.S. Customs agents at ports, and
concerns had arisen that versions offered on Internet sites may be not be
authentic. As long as Boehringer Ingelheim holds the FDA’s grant of marketing exclusivity in the U.S., it should not be expected to be sold as a reduced price generic drug.

Notwithstanding
these limited alternatives to paying the retail price for Vetmedin,
pimobendan is available through an accredited compounding pharmacy on the
Internet, Premier
Pharmacy Labs, Inc., in dosages different from the limited choices
offered by Boehringer Ingelheim for Vetmedin, including flavored oral
liquids and capsules sized to order. Veterinarians' prescriptions are
required.

Several veterinary research studies of pimobendan have been published
leading up to the FDA’s report. In studies of dogs with mitral
regurgitation, it has shown improved survival, heart and respiratory rate,
and left atrial size, without evidence of arrhythmogenesis. It has been
compared favorably with ramipril in
a March 2005 study report. In
a
March/April 2006 study report, Texas A&M University Drs.
Sonya G. Gordon, Matthew W. Miller, and Ashley B. Saunders find that "pimobendan is safe,
well tolerated, and leads to enhanced quality of life in dogs with CHF
secondary to...chronic valvular disease when used in combination with
furosemide or other conventional therapies (e.g., angiotensin-converting
enzyme inhibitors, digoxin)" and that "ongoing studies are evaluating its
effects on mortality associated with chronic valvular disease." See
Veterinary Resources for citations.

In
July 2008,
Drs. Häggström, Boswood, O'Grady and several others
reported that in a comparison study of pimobendan and benazepril
hydrochloride (the QUEST Study): "Pimobendan plus
conventional therapy prolongs time to sudden death, euthanasia for cardiac
reasons, or treatment failure in dogs with CHF caused by MMVD [myxomatous
mitral valve disease] compared with benazepril plus conventional therapy."
Of the 190 dogs, the median time to death (called the "endpoint") was 267
days for pimobendan and 140 days for benazepril. They concluded that "the
benefit of pimobendan persisted after adjusting for all baseline variables.
A longer time to reach the endpoint was also associated with being a
cavalier King Charles Spaniel, requiring a lower furosemide dose, and having
a higher creatinine concentration." In a
September 2013
follow-up analysis of the same QUEST Study patients, the same
researchers also found that the two medications resulted in similar quality
of life during the study. However, they found that pimobendan conferred
increased time before the progression of CHF and resulted in smaller heart
size, higher body temperature, and less retention of water.

In an
October 2013 report issued by Swedish cardiologists J. Häggström,
P.F. Lord, K. Höglund, I. Ljungvall, O. Jöns, C. Kvart and
K. Hansson, they studied 16 dogs in congestive heart failure (CHF)
due to mitral valve disease, including eleven cavaliers, They compared
pimobendan to benazepril and found that in dogs with CHF caused by MVD,
pimobendan significantly reduces the heart rate (HR), left ventricle (LV)
and atrium (LA) dimensions, heart rate-normalized pulmonary transit time (nPTT),
and N-terminal proatrial natriuretic peptide (NT-proANP), and increases the
ejection fraction, in comparison to benazepril. The reduction in heart size
in response to pimobendan treatment in dogs with CHF is in agreement with
previous studies, but reductions in HR, NT-proANP, and nPTT in response to
pimobendan treatment have not previously been described in naturally
occurring MVD.

The dangers of giving pimobendan to dogs not yet in
heart failure

Pimobendan also is being considered for cavaliers just
beginning to develop heart failure and even in earlier stages of
MVD. In October 2010,
an International team of cardiologists began a study (the "EPIC Trial")
giving Vetmedin (pimobendan) to cavaliers and other breeds with low grade MVD murmurs to see
if the drug will slow the progression of MVD to heart failure.
About 300 dogs are participating, with half receiving pimo and the other
half a placebo. The EPIC Trial is due to be completed in 2015.

Despite this "EPIC Trial", great caution should be taken when considering
treating any dog suffering only from mild, asymptomatic MVD. There is
evidence from recent studies that treatment with pimobendan of dogs not in
CHF may accelerate the symptoms of MVD, including increased regurgitation of
blood through the mitral valve, deterioration of the chordae tendinea, and
enlargement of the left side of the heart. Most recently, in
the 2007 French study,
"Comparative Adverse Cardiac Effects of Pimobendan and Benazepril
Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A
Prospective, Controlled, Blinded, and Randomized Study", the researchers
found (a) "increased systolic function in the PIMO group by comparison to
baseline value as assessed by fractional shortening"; (b) "the maximum area
and peak velocity of the regurgitant jet signal increased, whereas these
variables remained stable in the BNZ group"; (c) "histologic grades of
mitral valve lesions were more severe in the PIMO group than in the BNZ
group"; and (d) "acute focal hemorrhages, endothelial papillary hyperplasia,
and infiltration of chordae tendinae with glycosaminoglycans were observed
in the mitral valves of dogs from the PIMO group but not in those of the BNZ
group." They concluded:

"This study demonstrates that long-term administration of PIMO in dogs
with asymptomatic MVD is associated with an increase in systolic function
and, concomitantly, a progressive worsening of MVD with development of
specific mitral valve lesions."

Bottom line: pimobendan is hazardous
to the health of cavaliers with MVD murmurs but no symptoms.

See also
the 2005 study"Increased Mitral Valve Regurgitation and Myocardial Hypertrophy in Two Dogs
With Long-Term Pimobendan Therapy", in which normal doses of
pimobendan were determined to have increased mitral valve regurgitation and
caused ventricular hypertrophy. Read also warning comments by Drs.
Amara Estrada,
Mark Rishniw, and
George A. Kramer.

In
a 2007 study, "Evaluation of
Pimobendan in the Treatment of Early Mitral Valve Disease", the researchers
concluded from their study of 26 dogs that their "data suggest a possible
non-sustained positive inotropic effect and a reduction of the (mitral
regurgitation fraction) at 90 days with the administration of pimobendan in
early chronic MVD." They concluded, however, that more data are needed to
further assess their findings. A positive inotropic effect means that the
drug increases the strength with which the heart muscle contracts.

Dogs with CHF treated with pimobendan also have been found to live
longer. In a July 2006 Swedish study of 76 dogs with acquired atrioventricular valvular disease, sponsored by Boehringer Ingelheim, the
manufacturer of Vetmedin, which is pimobendan's brand name, researchers
report that dogs treated with benazepril hydrochloride, an ACE inhibitor,
lived an average of 128 days, while those treated with pimobendan lived an
average of 415 days, a difference between four months and thirteen months.
The study reportedly also found that within seven days of treatment with
pimobendan, over half of the dogs were symptom free. Most of the dogs were
treated concurrently with furosemide.

To the contrary, in
an October 2006 report, University of Georgia
internal medicine specialists Drs. Justin D. Thomason and Clay Calvert
conclude that pimobendan may benefit dogs with congestive heart failure
secondary to dilated cardiomyopathy or valvular insufficiency, only when
used in conjunction with other cardiac drugs, such as ACE inhibitors.

Possible negative side effects of pimobendan include ventricular
arrhythmias, particularly in dogs previously diagnosed with that
disorder. However, in
a 2007 study by Canadian
Drs. M. Lynne O'Sullivan,
Michael R. O'Grady, and C. Walker, which included eight cavaliers out of 23
dogs, they concluded that "Pimobendan did not result in an increase in
frequency of ventricular arrhythmias in comparison to benazepril."

Often, the cavalier in the late stage of congestive heart failure suffers
from a progressive deterioration of the quality of its life, which is due to
the combination of an inability to comfortably keep the dog free from fluid
congestion in its heart, lungs, and abdominal cavity, together with enlarged
heart chambers, lethargy, collapse, and deterioration of its kidney and/or
liver functions. Eventually diuretics, ACE inhibitors, other drugs, and even
pimobendan, no longer are able to remove enough of the fluids and increase
the supplies of blood and oxygen to the heart. This is a Stage D dog under
the 2009 ACVIM
Consensus Statement.

A good general health supplement for older dogs in congestive heart
failure is N, N-Dimethylglycine
(DMG). Vetri-DMG is a pure DMG product offered by Vetri-Science Laboratories
of Vermont. DMG is said to support the immune system,
promote oxygen utilization, improve cardiovascular function, support liver
function, and support ocular health.

--- appetite stimulants

General nutrition is very important. cavaliers at this advanced stage may
suffer severe weight loss, called progressive cardiac cachexia, and they
should be fed any palliative food to maintain muscle mass. Cardiologists may
prescribe an appetite stimulant, such as mirtazapine (Remeron) or
meclizine
(Antivert, Bonine, Dramamine II, Driminate II).

--- bronchial dilators

Dogs with severe flooding of the lungs should not be exerted in any way.
Some cardiologists may prescribe a bronchial dilator (bronchodilator), such as a
methylxanthine, for example, aminophylline,
oxtriphylline, theophylline (Corvental, Apo-Theo-LA), or
terbutaline (Brethine, Bricanyl) which are human grade
prescription medications which relax and open air passages in the lungs,
making breathing easier.* A narcotic, hydrocodone bitartrate (Hydodan,
Tussigon, Mycodone), may be prescribed to suppress the coughing by
affecting the brain's cough centers.

* Note:
Fluoroquinolone antibiotics should not be given concurrently with any
methylxanthines.

The onset of acute pulmonary edema requires
immediate recognition and therapy, including oxygen treatment, in order to
save the dog's life. (See the
Darcy's Daily Blog entry dated 8/25/06 for details of symptoms requiring
oxygen treatment.) Retained fluids (ascites), which fill the peritoneal
cavity of the abdomen due to tricuspid valve deterioration, may be removed periodically by aspiration with a
hypodermic needle (abdominocentesis).

--- avoid vaccines

Some cardiologists recommend that dogs with advanced mitral valve
disease not be vaccinated with the usual serums, including rabies, because
of possible adverse reactions which might accelerate damage to the dogs'
hearts. In such cases, the veterinarians will write letters to the county
licensing authorities which require periodic vaccinations, and in many
instances, the counties will accept the cardiologists' letters and excuse
the dogs from having to be vaccinated. There is a large body of research,
much of which may be found on the Internet, on the questions of vaccinosis
and other health problems attributed to annual or other periodic
vaccinations, particularly immune-mediated disorders.

--- euthanasia

At this stage of deterioration, inability to breathe, and suffering, the
owner may elect euthanasia, rather than to allow the dog to continue to
suffer.

UK cardiologist Simon Swift
(now at the University of Florida) noted at a 2010 symposium that:

"Interestingly, asymptomatic dogs fed a 'heart diet' had
a reduction in heart size. The 'heart diet' included decrease sodium,
increased levels of arginine, carnitine and taurine as well as
supplementation with omega 3 fatty acids. Whether this translates into a
delay before heart failure develops remains to be proven."

The Heart Diet was reported in a 2006 article
by Drs. Lisa M. Freeman (board certified veterinary
nutritionist) and John E. Rush (board certified veterinary
cardiologist), and by Peter J. Markwell (senior veterinary
nutritionist at a UK dog food company). They fed "a moderately reduced sodium
diet enriched with antioxidants, n-3 fatty acids, taurine, carnitine, and
arginine" for four weeks to fourteen dogs, including cavaliers, with
asymptomatic mitral valve disease. Another fifteen asymptomatic dogs, including
cavaliers, were fed a placebo. They found that the dogs on the heart diet had
measurable reductions in heart size, including the left-atrial dimension and
left-ventricular internal dimension.

A downside of this 2006 study was that the food fed in both diets consisted
of "commercial, extruded, dry dog foods", i.e., kibble. Another downside is that the study was funded by Mr. Markwell's employer,
a kibble manufacturer.

Two studies are being conducted to find medications directed at the
pathology of mitral valve disease and which may slow the progression of MVD.

--- serotonin blockers

One of the two studies involves blocking the cavalier's excessive
production of serotonin. Research thus far has suggested that: (a) serotonin
(5HT) activates growth activity in canine mitral valves; (b) dogs with MVD
have more serotonin receptors in their valve cells than other dogs; (c)
mitral valve cells have the capacity to make their own serotonin; and (d)
cavaliers also have a higher level of serotonin in their bloodstream. See,
e.g., this June 2011
report.

Researchers are exploring the possibility that if serotonin levels can be
reduced, by blocking the receptors in the mitral valves, then the
progression of the deterioration of the valves and their leaflets can be
slowed. One existing drug, approved for use by humans in Europe, is
being tested on dogs with MVD to determine its effectiveness in reducing the
level of serotonin and slowing the progression of MVD in cavaliers.

--- beta blockers

The other study involves a beta blocker intended to slow the progression
of MVD. This study is being conducted at veterinary schools and some
cardiology clinics throughout the United States. The researchers need
participating dogs.
See details
below.

A few veterinary surgery centers have experimented with surgically
repairing the mitral valves or replacing either the mital valve tendons (chordae tendineae)
or the valve leaflets with implants, such as pig or cow heart valves or
mechanical devices.

Other surgeons have replaced chordae tendineae and valve leaflets with
polytetrafluoroethylene (PTFE) and expanded
polytetrafluoroethylene (ePTFE) implants are made of a carbon and
fluorine based synthetic polymer (Gore-Tex and
SoftForm) that is biologically inert and non-biodegradable in the
body. In a 2012 article, Japanese
veterinary surgeons report that using ePTFE "has excellent tissue
compatibility and durability and can be effectively used for canine mitral
valve repair."

In a March 2012 report,
Japanese veterinary heart surgeon
Dr. Masami Uechi (left) states that open-heart mitral
valve repair consisting of installing a ring around the valve, a procedure
called mitral annuloplasty, and/or replacing chordae tendineae with durable,
artificial chordae have improved long-term clinical outcomes in small breed
dogs, without the need for long-term anti-clotting therapies. He reported
that post-operative improvements have included reduced regurgitation,
decrease in heart size, reduction in murmur grade, improved appetite,
elimination of cough, dyspnea, and anorexia.

In a
September 2014 paper before the WSAVA Congress, Dr. Isamu Kanemoto
summarized the current methods of mitral valve surgeries and their
pitfalls for small dogs.

The box below lists locations where mitral valve
surgeries have been performed, with details about their techniques, success
rates, and costs.

Canine Heart Valve Replacement & Repair Surgery

• DAVIS, CA:
Dr. Leigh Griffiths, board certified veterinary cardiologist and
surgeon, of the University of California at Davis' Veterinary Medical
Teaching Hospital heads the UC Davis Cardiovascular Surgery Program, which
includes canine mitral valve repair and replacement. He does not recommend
implanting mechanical valves, due to the necessity of life-long
anti-coagulation therapy and the threat of clotting in the event of any
lapses in therapy. His group performs valve tissue replacement surgery,
using either glutaraldehyde fixed porcine aortic or bovine pericardial
valves. Dr. Griffiths warns that foreign tissue rejection is possible, and
so he currently only recommends tissue valve placement in patients where
valve repair is considered impossible.

Dr. Griffiths reports that the success rate of mitral repair is 70% of
dogs surviving to leave the hospital, and of those which survive, the
disease is essentially cured in 70%. Among the 30% which are not cured, he
says that the disease is arrested (no more progression and stable
medications) and they almost always die of other non-cardiac disease. So he
rates surgery as very successful, but with a high initial risk. They do one
open heart procedure a month. Cost of the procedure is from $12,000-
to $14,000. Read more about this program at
its website.

• FT. COLLINS, CO: Dr. E. Christopher Orton of the James
L. Voss Veterinary Teaching Hospital at Colorado State University (CSU) in
Ft. Collins, Colorado, heads an animal cardiac surgery program which
reportedly has consistently and successfully completed life-saving,
open-heart surgeries on canines. Dr. Orton and his surgical team have
performed over 100 open-heart surgeries since1991 and began replacing heart
valves in 1997. Valve surgery requires a team of six to eight people,
additional staff in the critical care unit, and intensive monitoring of the
dog before, during, and immediately after surgery, which limits the team's
ability to conduct surgeries to only a few per month. The team replaces the
defective valve with an artificial heart valve made from bovine pericardial
tissue or with a mechanical valve prosthesis. The surgical procedure
typically lasts about five hours, during which the new valve is placed in
the dog's heart while its blood circulates through a heart-lung machine;
then its heart is re-started, after which the dog is monitored in the
surgical suite for two hours. The patient then is placed in the hospital's
intensive care unit, where it is closely monitored for the next 72 hours.

The dog has to be monitored carefully for several months after it is
discharged from the surgical unit. The surgery offers the dog the
possibility of a lifelong cure, as long as the prosthetic valve continues to
function well and does not develop complications, such as blood clots or
tissue rejection. Dr. Orton's reports on his team's studies are cited below
in Veterinary Resources. See 2004 MVD Surgery Report and 2005 MVD Surgery
Report.

Beginning in July 2011, Dr. Orton and board certified veterinary
cardiologist Dr.
Allison K. Adams have been conducting clinical trials replacing
the mitral valve with an artificial heart valve (right) called MitralSeal
developed by Avalon Medical, Ltd. This mechanical valve is designed to be installed
using a minimally invasive approach into the beating heart.

Watch
an animated demonstration of the installation of a MitralSeal valve on
YouTube here (or click the YouTube icon at left).

• PITTSBURGH,
PA: Research physicians at the University of Pittsburgh have
conducted experimental mitral valve repairs on dogs, using radiofrequency
ablation (RFA). The RFA energy is applied to the deteriorating valve
flaps and chords, resulting in controlled damage which has the affect of
qualitatively reducing the leaflet surface and the chordal length. The
researchers found that the result of the application of RFA was to reduce
the mitral regurgitation by statistically significant amounts.
Read the details
below.

• COLLEGE
STATION, TX: Dr. David A. Nelson of the Small Animal Medicine and
Surgery Center at Texas A&M's College of Veterinary Medicine leads a similar
veterinary surgical team which specializes in canine open heart surgery,
including mitral valve repair. The surgical center is a part of the Michael
E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical
Devices. It is researching effective ways to repair the valves, rather than
replace them, in smaller dogs.

Dr. Nelson advises that, to be eligible for surgery, the dog's heart
function must still be preserved. Dogs that have reached the end point of a
lengthy cardiac disease cycle are not considered as candidates. The total
number of cases performed is still too low to offer any probability of
success. There are still great risks involved, and each dog's case is
different. A normal healthy young dog could likely undergo and recover from
cardiac surgery without complication. One that is older, with cardiac
disease or other organ involvement, presents a much more difficult
challenge.

All candidates are referred by veterinarians, who will make the first
contact to with the Texas A&M surgical team and send pertinent medical
information that allows the team to make an initial determination. A cardiac
work-up examination of the dog then is scheduled. The work-up may be
scheduled in connection with a tentative surgery date. However, only after
the work-up and consultation with the team is a final decision made as to
recommend surgery.

A modest amount of mitral valve leakage may continue following the
successful surgical mitral valve repair. Changing the disease from a rapidly
progressive one to a static, manageable situation is considered a very
acceptable result. Following surgery, the dog may remain on some cardiac
medications.

The costs of surgery and aftercare is determined on a case by case basis.
A current range of costs is from $5,000.00 to $10,000.00 or higher. Higher
costs usually are due to increased intensive care unit charges. The team
will make an accurate estimate after the dog's cardiac work-up examination.
Due to the nature and expense of the service, the surgical center requires a
deposit of $4,500.00 prior to surgery. Conventional types of credit cards
are acceptable.

Dr. Nelson may be reached by telephone at 979-845-2351 and email
dnelson@cvm.tamu.edu The surgical team's website is http://kndn.com/cv/

• LONDON,
ENGLAND, UK: Heart surgeon Dan Brockman (BVSc,
CVR, CSAO, MRCVS, Diplomate ACVS/ECVS) at the Royal Veterinary College,
University of London, in England, has begun a animal cardiac surgery
program, which includes open-heart mitral valve surgeries on canines. He has
consulted with Dr. Orton at Colorado State University, and the two surgeons
have been working together to advance heart surgeries in the UK.

Mr. Brockman may be reached at The Queen Mother Hospital for Animals,
Hawkshead Campus, the Royal Veterinary College, telephone +44 (0)1707
666366, email qmhreception@rvc.ac.uk The website is
www.rvc.ac.uk/Hospitals/QMH/Index.cfm

While two of their CKCS patients died during the
post-operative study due to complications, and three were diagnosed with
syringomyelia, the researchers found that among the nine survivors, "at 1
and 3 months after surgery, the left atrial to aortic root diameter ratio
... and the plasma atrial natriuretic peptide level ... were lower than
those before surgery ... There were also significant improvements in the
number of prescribed cardiovascular drugs 1 month after surgery ... and in
the cardiac murmur grade ... ."

• TOKYO,
JAPAN: Drs. Midori Akiyama, Ryou Tanaka, Kohji Maruo, and
Yoshihisa Yamane, of the Department of Veterinary Surgery, Tokyo
University of Agriculture and Technology, in Tokyo, Japan, have conducted
mitral valve repair surgery on at least one small dog, a 6-month-old, 15.6
lb., male Shiba Inu. They write in their 2005 article: A 6-month-old, 15.6
lb., male Shiba Inu with a cardiac murmur "due to an ostium primum septal
defect, a ventricular septal defect, and mitral valve malformation with
regurgitation. The mitral valve and tricuspid valve were separated and
displaced at the same level as the ventricular septum. The mitral valve had
a cleft in the septal cusp. ... An incision was made in the right atrium,
and an ASD (25 x 15 mm in diameter) was identified in the lower portion of
the atrial septum immediately above the ventricular septum. The mitral valve
was seen through the ASD, and there was a cleft in the septal cusp. The
cleft separated the septal cusps into two portions, both of which had thick
edges. The cleft was repaired with mattress sutures of 5-0 polypropylenes.
The ASD was then closed with sutures of 5-0 polypropylene using pledgets. A
small VSD (5 mm in diameter) was observed behind the septal cusp of the
tricuspid valve. The VSD was closed with simple mattress sutures of 5-0
polypropylene. The right atrium was sutured closed with a simple continuous
pattern of 5-0 polypropylene." See their 2005 journal article. Their clinic
is located at Department of Veterinary Surgery, Faculty of Agriculture,
Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi,
Tokyo, 183-8509, Japan; website: www.tuat.ac.jp/index-e.html

In
research, an implanted attachment to the mitral valve, called an "epicardial mitral annuloplasty device", has been
inserted on dogs' beating hearts in less than 30 seconds and without the need for cardiopulmonary
bypass surgery. In two published reports by researchers at the Cleveland
Clinic (January
2010 and
December 2010), the device (right) reduced the septal-lateral (S-L)
dimension of the mitral annulus (the ring that is attached to the mitral
valve leaflets) and eliminated the backflow of blood through the mitral
valve, without requiring
the use of a cardiopulmonary bypass procedure. See the diagram
below.

The device, called Mitral Touch, has been manufactured by
MAQUET Cardiovascular LLC of San Jose, California. It consists of a
titanium wire backbone, silicone bulking, and polyester fabric cover
with a flap of 1 cm for securing it to the heart. The device is secured
with titanium helical tacks driven through the device into the
ventricular wall.

In a
2014 report on what appears to be the same device but now
manufactured by Infiniti Medical and called Mitrex,
researchers reported the results of a six month trial of the device implanted
on the beating hearts of ten swine. Necropsy was performed at 180 days. The researchers
found that:

"Coronary flow, ejection fraction, left
ventricular wall motion and mitral valve function were normal post
implantation and at term. ... Devices were well tolerated causing only
minimal to mild fibrosis and chronic inflammation. No significant
changes were observed in the myocardium except for muscle fiber atrophy
near the tip of the anterior arm. There appeared to be ample tissue over
the tip and no danger of perforation in all but one subject. No
meaningful changes were noted in cardiac shape, ventricular wall
thickness, chamber size, heart valves, and blood vessels. The myocardial
compression necessary to perform epicardial annuloplasty was well
tolerated. The Mitrex device was safe and biocompatible."

In
a
June 2013 study by a team of US cardiologists, they found that
injecting alginate hydrogel directly into the left
ventricle (LV) of the hearts of 7 dogs in advanced heart failure,
increased the thickness of the LV wall, and LV structure and function
improved. Alginate is a naturally derived polysaccharide that is used in
drug delivery and as cell encapsulation material. The brand name
Algisyl-LVR is manufactured by LoneStar Heart, Inc. of Laguna
Hills, California.

Dogs with mitral valve disease have an increased anesthetic risk.
Pre-anesthetic evaluation, premedication, induction, maintenance of
anesthesia (anaesthesia), and monitoring of anesthetized dogs and
possible complications need to be taken into account. An excellent
review of all aspects of anesthetizing dogs with MVD is discussed in this
2012 article by Austrian veterinarians Drs. Roswitha Steinbacher and
René Dörfelt.

Early-onset mitral valve disease has been found to be
"highly heritable" in the cavalier King Charles spaniel breed, and
"selection against the disease should be successful.", according to an
April 2010
research report.

Due to the pervasiveness of MVD in the breed worldwide, cavalier King
Charles spaniels under the age of five years should not be bred (with one
limited exception -- see MVD Breeding Protocol). Also, no
cavalier should be
bred after age five years if it developed an MVD murmur before the age of
five years. Any littermates of breeding stock having early-onset MVD (mitral
valve murmurs before age 5 years) should be taken into very serious
consideration. All CKCS breeding stock should be examined by
board certified
veterinary cardiologists at least annually and cleared by the veterinary
specialists for MVD, the closer the examination to the breeding the better.
It is recommended that all cavaliers, breeding stock or not, be examined
annually by board certified veterinary cardiologists after age one year. See
the current list of health clinics for upcoming cardiologist examinations.

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